Bicyclic amide compounds and methods of use thereof

ABSTRACT

The invention provides novel compounds having the general formula I: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , the A ring and the B ring are as described herein, pharmaceutical compositions including the compounds and methods of using the compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/429,558, filed on Dec. 2, 2016, the entire contents of which arehereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a mammal, and in particular to inhibitors of RIP1kinase useful for treating diseases and disorders associated withinflammation, cell death and others.

BACKGROUND OF THE INVENTION

Receptor-interacting protein-1 (“RIP1”) kinase is a serine/threonineprotein kinase. RIP1 is a regulator of cell signaling that is involved,among other things, in the mediation of programmed cell death pathways,e.g., necroptosis. The best studied form of necroptotic cell death isinitiated by TNFα (tumor necrosis factor), but necroptosis can also beinduced by other members of the TNFα death ligand family (Fas andTRAIL/Apo2L), interferons, Toll-like receptors (TLRs) signaling andviral infection via the DNA sensor DAI (DNA-dependent activator ofinterferon regulatory factor) [1-3], Binding of TNFα to the TNFR1 (TNFreceptor 1) prompts TNFR1 trimerization and formation of anintracellular complex, Complex-I. TRADD (TNF receptor associated deathdomain protein) binds to the intracellular death domain of TNFR1 andrecruits the protein kinase RIP1 (receptor-interacting protein 1)through the death domain present in both proteins [4], Following initialrecruitment into TNFR1-associated signaling complex, RIP1 translocatesto a secondary cytoplasmatic complex, Complex-II [5-7], Complex-II isformed by the death domain containing protein FADD (Fas-associatedProtein), RIP1, caspase-8 and cFLIP. If caspase-8 is not fully activatedor its activity is blocked, the protein kinase RIP3 gets recruited tothe complex, forming a necrosome, which will lead to necroptotic celldeath initiation [8-10], Once the necrosome is formed, RIP1 and RIP3engage in a series of auto and cross phosphorylation events that areessential for necroptotic cell death. Necroptosis can be completelyblocked either by the kinase inactivating mutation in any of the twokinases, or chemically by RIP1 kinase inhibitors (necrostatins), or RIP3kinase inhibitors [11-13], Phosphorylation of RIP3 allows the bindingand phosphorylation of pseudokinase MLKL (mixed lineage kinasedomain-like), a key component of necroptotic cell death [14, 15].

Necroptosis has crucial pathophysiological relevance in myocardialinfarction, stroke, atherosclerosis, ischemia-reperfusion injury,inflammatory bowel diseases, retinal degeneration and a number of othercommon clinical disorders [16], Therefore, selective inhibitors of RIP1kinase activity are therefore desired as a potential treatment ofdiseases mediated by this pathway and associated with inflammationand/or necroptotic cell death.

Inhibitors of RIP1 kinase have been previously described. The firstpublished inhibitor of RIP1 kinase activity was necrostatin 1 (Nec-1)[17], This initial discovery was followed by modified versions of Nec-1with various abilities to block RIP1 kinase activity [11, 18], Recently,additional RIP1 kinase inhibitors have been described that differstructurally from necrostatin class of compounds [19, 20, 21].

References cited above, each of which is hereby incorporated byreference in its entirety:

-   1) Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S.,    Walczak, H. and Vandenabeele, P. (2014) Regulated necrosis: the    expanding network of non-apoptotic cell death pathways. Nature    reviews. Molecular cell biology. 15, 135-147.-   2) Newton, K. (2015) RIPK1 and RIPK3: critical regulators of    inflammation and cell death. Trends in cell biology. 25, 347-353.-   3) de Almagro, M. C. and Vucic, D. (2015) Necroptosis: Pathway    diversity and characteristics. Semin Cell Dev Biol. 39, 56-62.-   4) Chen, Z. J. (2012) Ubiquitination in signaling to and activation    of IKK. Immunological reviews. 246, 95-106.-   5) O'Donnell, M. A., Legarda-Addison, D., Skountzos, P., Yeh, W. C.    and Ting, A. T. (2007) Ubiquitination of RIP 1 regulates an    NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol.    17, 418-424.-   6) Feoktistova, M., Geserick, P., Kellert, B., Dimitrova, D. P.,    Langlais, C., Hupe, M., Cain, K., MacFarlane, M., Hacker, G. and    Leverkus, M. (2011) cIAPs block Ripoptosome formation, a    RIP1/caspase-8 containing intracellular cell death complex    differentially regulated by cFLIP isoforms. Molecular cell. 43,    449-463.-   7) Bertrand, M. J., Milutinovic, S., Dickson, K. M., Ho, W. C.,    Boudreault, A., Durkin, J., Gillard, J. W., Jaquith, J. B.,    Morris, S. J. and Barker, P. A. (2008) cIAP1 and cIAP2 facilitate    cancer cell survival by functioning as E3 ligases that promote RIP1    ubiquitination. Mol Cell. 30, 689-700.-   8) Wang, L., Du, F. and Wang, X. (2008) TNF-alpha induces two    distinct caspase-8 activation pathways. Cell. 133, 693-703.-   9) He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L. and    Wang, X. (2009) Receptor interacting protein kinase-3 determines    cellular necrotic response to TNF-alpha. Cell. 137, 1100-1111.-   10) Cho, Y. S., Challa, S., Moquin, D., Genga, R., Ray, T. D.,    Guildford, M. and Chan, F. K. (2009) Phosphorylation-driven assembly    of the RIP1-RIP3 complex regulates programmed necrosis and    virus-induced inflammation. Cell. 137, 1112-1123.-   11) Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I. L., Korkina,    O., Teng, X., Abbott, D., Cuny, G. D., Yuan, C., Wagner, G.,    Hedrick, S. M., Gerber, S. A., Lugovskoy, A. and Yuan, J. (2008)    Identification of RIP1 kinase as a specific cellular target of    necrostatins. Nat Chem Biol. 4, 313-321.-   12) Newton, K., Dugger, D. L., Wickliffe, K. E., Kapoor, N., de    Almagro, M. C., Vucic, D., Komuves, L., Ferrando, R. E., French, D.    M., Webster, J., Roose-Girma, M., Warming, S. and    Dixit, V. M. (2014) Activity of protein kinase RIPK3 determines    whether cells die by necroptosis or apoptosis. Science. 343,    1357-1360.-   13) Kaiser, W. J., Sridharan, H., Huang, C., Mandal, P., Upton, J.    W., Gough, P. J., Sehon, C. A., Marquis, R. W., Bertin, J. and    Mocarski, E. S. (2013) Toll-like receptor 3-mediated necrosis via    TRIF, RIP3, and MLKL. The Journal of biological chemistry. 288,    31268-31279.-   14) Zhao, J., Jitkaew, S., Cai, Z., Choksi, S., Li, Q., Luo, J. and    Liu, Z. G. (2012) Mixed lineage kinase domain-like is a key receptor    interacting protein 3 downstream component of TNF-induced necrosis.    Proceedings of the National Academy of Sciences of the United States    of America. 109, 5322-5327.-   15) Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang,    L., Yan, J., Liu, W., Lei, X. and Wang, X. (2012) Mixed Lineage    Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of    RIP3 Kinase. Cell. 148, 213-227.-   16) Linkermann, A. and Green, D. R. (2014) Necroptosis. The New    England journal of medicine. 370, 455-465.-   17) Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P.,    Mizushima, N., Cuny, G. D., Mitchison, T. J., Moskowitz, M. A. and    Yuan, J. (2005) Chemical inhibitor of nonapoptotic cell death with    therapeutic potential for ischemic brain injury. Nat Chem Biol. 1,    112-119.-   18) Takahashi, N., Duprez, L., Grootjans, S., Cauwels, A., Nerinckx,    W., DuHadaway, J. B., Goossens, V., Roelandt, R., Van Hauwermeiren,    F., Libert, C., Declercq, W., Callewaert, N., Prendergast, G. C.,    Degterev, A., Yuan, J. and Vandenabeele, P. (2012) Necrostatin-1    analogues: critical issues on the specificity, activity and in vivo    use in experimental disease models. Cell Death Dis. 3, e437.-   19) Harris, P. A., Bandyopadhyay, D., Berger, S. B., Campobasso, N.,    Capriotti, C. A., Cox, J. A., Dare, L., Finger, J. N., Hoffman, S.    J., Kahler, K. M., Lehr, R., Lich, J. D., Nagilla, R., Nolte, R. T.,    Ouellette, M. T., Pao, C. S., Schaeffer, M. C., Smallwood, A.,    Sun, H. H., Swift, B. A., Totoritis, R. D., Ward, P., Marquis, R.    W., Bertin, J. and Gough, P. J. (2013) Discovery of Small Molecule    RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated    with Necroptosis. ACS medicinal chemistry letters. 4, 1238-1243.-   20) Najjar, M., Suebsuwong, C., Ray, S. S., Thapa, R. J., Maki, J.    L., Nogusa, S., Shah, S., Saleh, D., Gough, P. J., Bertin, J., Yuan,    J., Balachandran, S., Cuny, G. D. and Degterev, A. (2015) Structure    Guided Design of Potent and Selective Ponatinib-Based Hybrid    Inhibitors for RIPK1. Cell Rep.-   21) International Patent Publication No. WO 2014/125444.

SUMMARY OF THE INVENTION

Provided herein are compounds of formula I:

or pharmaceutically acceptable salts thereof, whereinR¹ and R²:

-   -   (a) are each independently selected from the group consisting of        C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,        C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, C₁-C₆ alkyl-N(R^(N))₂,        phenyl, 5 to 6 membered heteroaryl, and 4 to 5 membered        heterocyclyl;    -   (b) together with the adjacent amide N, form a 4 to 7 membered        unsaturated heterocyclic ring optionally substituted by one or        two R³, wherein the unsaturated heterocyclic ring contains zero        or one additional heteroatom selected from the group consisting        of NR^(N), O and S; or    -   (c) together with the adjacent amide N, form a bicyclic        heteroaryl moiety optionally substituted by one or two R³,        wherein the bicyclic heterocyclic moiety contains zero to three        additional heteroatoms selected from the group consisting of N,        O and S, wherein only one of the additional heteroatoms is O or        S;        each R³ is independently selected from the group consisting of        F, Cl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl, and phenoxy; or,        when R¹ and R² together with the adjacent amide N form a 6        membered ring, two R³ may together form a 1 to 2 carbon bridge        or a C₃-C₅ spirocycloalkyl;        each R^(N) is independently selected from the group consisting        of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy and C₁-C₆        haloalkyl; or two R^(N) may together with the adjacent N form a        4-6 membered ring;        the A ring is a 5 or 6 membered heteroaryl having 1 to 3        heteroatoms selected from the group consisting of nitrogen,        oxygen and sulfur; wherein the A ring is optionally substituted        with 1 to 2 substituents selected from the group consisting of        halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy and C₁-C₆ haloalkoxy; and wherein if a nitrogen atom in        the A ring is substituted, the substituent is not halogen, C₁-C₆        alkoxy or C₁-C₆ haloalkoxy having an oxygen or sulfur atom        directly bonded to the nitrogen atom;        the B ring is a 5 to 7 membered cycloalkyl, or a 5 to 7 membered        heterocyclyl having 1 to 3 heteroatoms selected from the group        consisting of nitrogen, oxygen and sulfur; wherein the B ring is        substituted according to (a), (b), or both (a) and (b):    -   (a) 1 to 2 substituents selected from the group consisting of        halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, C₁-C₆        alkyl-N(R^(N))₂, and cyano; wherein if a nitrogen atom in the B        ring is substituted, the substituent is not halogen, cyano, or a        C₁-C₆ alkoxy, C₁-C₆ haloalkoxy or C₁-C₆ thioalkyl having an        oxygen or sulfur atom directly bonded to the nitrogen atom;        wherein two substituents on the B ring together may form a 1 to        2 carbon bridge or C₃-C₅ spirocycloalkyl group;    -   (b) 1 substituent selected from the group consisting of phenyl,        benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl),        CH₂-(4 to 6 membered heterocyclyl), CH₂CH₂-(4 to 6 membered        heterocyclyl), 5 or 6 membered heteroaryl, and CH₂-(5 or 6        membered heteroaryl); wherein when a phenyl ring is present it        may be substituted by 1 or 2 substituents selected from the        group consisting of halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄        alkoxy, C₁-C₄ haloalkoxy, and cyano;        provided that if the B ring is substituted by only one        substituent, it is not halogen or methyl.

In the following description, all references to formula I also includesubembodiments of formula I (i.e., formulae 1a, 1b, etc.).

Also provided herein are pharmaceutical compositions comprising acompound of formula I, or a pharmaceutically acceptable salt thereof,and one or more pharmaceutically acceptable carriers or excipients.Specific embodiments include pharmaceutical compositions suitable forintravenous or oral delivery.

Also provided herein are oral formulations of a compound of formula I,or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers or excipients suitable for oraldelivery.

Also provided herein are parenteral formulations of a compound offormula I, or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable carriers or excipients suitable forparenenteral delivery.

In some embodiments, provided herein are uses of a compound of formulaI, or a pharmaceutically acceptable salt thereof, for the treatment ofdiseases and disorders. In some embodiments, the diseases and disordersto be treated are selected from the group consisting of irritable boweldisorders (IBD), irritable bowel syndrome (IBS), Crohn's disease,ulcerative colitis, myocardial infarction, stroke, traumatic braininjury, atherosclerosis, ischemia-reperfusion injury of kidneys, liverand lungs, cisplatin-induced kidney injury, sepsis, systemicinflammatory response syndrome (SIRS), pancreatits, psoriasis, retinitispigmentosa, retinal degeneration, chronic kidney diseases, acuterespiratory distress syndrome (ARDS), chronic obstructive pulmonarydisease (COPD).

In some embodiments, the disease or disorder to be treated is selectedfrom the group consisting of inflammatory bowel diseases (includingCrohn's disease and ulcerative colitis), psoriasis, retinal detachment,retinitis pigmentosa, macular degeneration, pancreatitis, atopicdermatitis, arthritis (including rheumatoid arthritis, osteoarthritis,spondylarthritis, gout, systemic onset juvenile idiopathic arthritis(SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE),Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome(APS), vasculitis, liver damage/diseases (non-alcohol steatohepatitis,alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliarydiseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity,hepatotoxicity), kidney damage/injury (nephritis, renal transplant,surgery, administration of nephrotoxic drugs e.g. cisplatin, acutekidney injury (AKI)), Celiac disease, autoimmune idiopathicthrombocytopenic purpura, transplant rejection, ischemia reperfusioninjury of solid organs, sepsis, systemic inflammatory response syndrome(SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction(MI), atherosclerosis, Huntington's disease, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinalmuscular atropy (SMA), allergic diseases (including asthma and atopicdermatitis), multiple sclerosis, type I diabetes, Wegener'sgranulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1converting enzyme (ICE, also known as caspase-1) associated feversyndrome, chronic obstructive pulmonary disease (COPD), tumor necrosisfactor receptor-associated periodic syndrome (TRAPS), periodontitis,NEMO-deficiency syndrome (F-kappa-B essential modulator gene (also knownas IKK gamma or IKKG) deficiency syndrome), HOIL-1 deficiency ((alsoknown as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1 deficiency),linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome,hematological and solid organ malignancies, bacterial infections andviral infections (such as tuberculosis and influenza), and Lysosomalstorage diseases (particularly, Gaucher Disease, and including GM2,Gangliosidosis, Alpha-mannosidosis, Aspartylglucosaminuria, CholesterylEster storage disease, Chronic Hexosaminidase A Deficiency, Cystinosis,Danon disease, Fabry disease, Farber disease, Fucosidosis,Galactosialidosis, GM1 gangliosidosis, Mucolipidosis, Infantile FreeSialic Acid Storage Disease, Juvenile Hexosaminidase A Deficiency,Krabbe disease, Lysosomal acid lipase deficiency, MetachromaticLeukodystrophy, Mucopolysaccharidoses disorders, Multiple sulfatasedeficiency, Niemann-Pick Disease, Neuronal Ceroid Lipofuscinoses, Pompedisease, Pycnodysostosis, Sandhoff disease, Schindler disease, SialicAcid Storage Disease, Tay-Sachs and Wolman disease).

In some embodiments, the diseases and disorders to be treated areselected from the group consisting of irritable bowel disorders (IBD),irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis,myocardial infarction, stroke, traumatic brain injury, atherosclerosis,ischemia-reperfusion injury of kidneys, liver and lungs,cisplatin-induced kidney injury, sepsis, systemic inflammatory responsesyndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa andretinal degeneration.

In some embodiments, provided herein are methods for the treatment orprevention of a disease or disorder with a therapeutically effectiveamount of a compound of formula I, or a pharmaceutically acceptable saltthereof, wherein the disease or disorder is associated with inflammationand/or necroptosis. In some embodiments said disease or disorder isselected from the specific diseases and disorders recited herein.

In some embodiments, provided herein are methods of inhibiting RIP1kinase activity by contacting a cell with a compound of formula I or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As provided herein, all chemical formulae and generic chemicalstructures should be interpreted to provide proper valence andchemically stable bonds between atoms as understood by one of ordinaryskill in the art. Where appropriate, substituents may be bonded to morethan one adjacent atom (e.g., alkyl includes methylene where two bondsare present).

In the chemical formulae provided herein, “halogen” or “halo’ refers toflurorine, chlorine, and bromine (i.e., F, Cl, Br).

Alkyl, unless otherwise specifically defined, refers to an optionallysubstituted, straight-chain or branched C₁-C₁₂ alkyl group. In someembodiments, alkyl refers to a C₁-C₆ alkyl group. Exemplary alkyl groupsinclude methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,tert-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-oxtyl.Substituted alkyl groups provided herein are substituted by one or moresubstituents selected from the group consisting of halogen, cyano,trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy,C₃-C₆ cycloalkyl, phenyl, OH, CO₂H, CO₂(C₁-C₄ alkyl), NH₂, NH(C₁-C₄alkyl), N(C₁-C₄ alkyl)₂, NH(C═O)C₁-C₄ alkyl, (C═O)NH(C₁-C₄ alkyl),(C═O)N(C₁-C₄ alkyl)₂, S(C₁-C₄ alkyl), SO(C₁-C₄ alkyl), SO₂(C₁-C₄ alkyl),SO₂NH(C₁-C₄ alkyl), SO₂N(C₁-C₄ alkyl)₂, and NHSO₂(C₁-C₄ alkyl). In someembodiments, the substituted alkyl group has 1 or 2 substituents. Insome embodiments, the alkyl group is unsubstituted.

Cycloalkyl, unless otherwise specifically defined, refers to anoptionally substituted C₃-C₁₂ cycloalkyl group and includes fused,spirocyclic, and bridged bicyclic groups, wherein the substituents areselected from the group consisting of halogen, cyano, trifluoromethyl,methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C₃-C₆ cycloalkyl,phenyl, OH, CO₂H, CO₂(C₁-C₄ alkyl), NH₂, NH(C₁-C₄ alkyl), N(C₁-C₄alkyl)₂, NH(C═O)C₁-C₄ alkyl, (C═O)NH(C₁-C₄ alkyl), (C═O)N(C₁-C₄ alkyl)₂,S(C₁-C₄ alkyl), SO(C₁-C₄ alkyl), SO₂(C₁-C₄ alkyl), SO₂NH(C₁-C₄ alkyl),SO₂N(C₁-C₄ alkyl)₂, and NHSO₂(C₁-C₄ alkyl). In some embodiments,cycloalkyl refers to a C₃-C₆ cycloalkyl group. In some embodiments, theC₃-C₆ cycloalkyl group is optionally substituted with 1 to three halogenatoms. In some embodiments, the C₃-C₆ cycloalkyl group is optionallysubstituted with 1 to three fluorine atoms. Exemplary C₃-C₆ cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Exemplary C₃-C₁₂ cycloalkyl groups further include bicyclo[3.1.0]hexyl,bicyclo[2.1.1]hexyl, cycloheptyl, bicycle[4.1.0]heptyl,spiro[4.2]heptyl, cyclooctyl, spiro[4.3]octyl, spiro[5.2]octyl,bicyclo[2.2.1]heptanyl, bicycle [2.2.2]octanyl, adamantanyl, decalinyl,and spiro[5.4]decanyl. Where appropriate, cycloalkyl groups may be fusedto other groups such that more than one chemical bond exists between thecycloalkyl group and another ring system (e.g., the C ring of formulaI). In some embodiments, the cycloalkyl group is unsubstituted.

Haloalkyl, unless otherwise specifically defined, refers to astraight-chain or branched C₁-C₁₂ alkyl group, wherein one or morehydrogen atoms are replaced by a halogen. In some embodiments, haloalkylrefers to a C₁-C₆ haloalkyl group. In some embodiments, 1 to 3 hydrogenatoms of the haloalkyl group are replaced by a halogen. In someembodiments, every hydrogen atom of the haloalkyl group is replaced by ahalogen (e.g, trifluoromethyl). In some embodiments, the haloalkyl is asdefined herein wherein the halogen in each instance is fluorine.Exemplary haloalkyl groups include fluoromethyl, difluoromethyl,trifluromethyl, trifluoroethyl, and pentafluoroethyl.

Alkoxy, unless otherwise specifically defined, refers to astraight-chain or branched C₁-C₁₂ alkyl group, wherein one or moreoxygen atoms are present, in each instance between two carbon atoms. Insome embodiments, alkoxy refers to a C₁-C₆ alkoxy group. In someembodiments, C₁-C₆ alkoxy groups provided herein have one oxygen atom.Exemplary alkoxy groups include methoxy, ethoxy, CH₂OCH₃, CH₂CH₂OCH₃,CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂OCH₂CH₂CH₃, CH₂CH₂CH₂OCH₃, CH₂OCH(CH₃)₂,CH₂OC(CH₃)₃, CH(CH₃)OCH₃, CH₂CH(CH₃)OCH₃, CH(CH₃)OCH₂CH₃, CH₂OCH₂OCH₃,CH₂CH₂OCH₂CH₂OCH₃, and CH₂OCH₂OCH₂OCH₃.

Cycloalkoxy, unless otherwise specifically defined, refers to a C₄-C₁₀or a C₄-C₆ alkoxy group as defined above wherein the group is cyclic andcontains one oxygen atom. Exemplary cycloalkoxy groups include oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl.

Haloalkoxy, unless otherwise specifically defined, refers to a C₁-C₆haloalkyl group as defined above, wherein one or two oxygen atoms arepresent, in each instance between two carbon atoms. In some embodiments,C₁-C₆ haloalkoxy groups provided herein have one oxygen atom. Exemplaryhaloalkoxy groups include OCF₃, OCHF₂ and CH₂OCF₃.

Thioalkyl, unless otherwise specifically defined, refers to a C₁-C₁₂ ora C₁-C₆ alkoxy group as defined above wherein the oxygen atom isreplaced by a sulfur atom. In some embodiments, thioalkyl groups mayinclude sulfur atoms substituted by one or two oxygen atoms (i.e.,alkylsulfones and alkylsulfoxides). Exemplary thioalkyl groups are thoseexemplified in the definition of alkoxy above, wherein each oxygen atomis replaced by a sulfur atom in each instance.

Thiocycloalkyl, unless otherwise specifically defined, refers to aC₄-C₁₀ or a C₄-C₆ thioalkyl group as defined above wherein the group iscyclic and contains one sulfur atom. In some embodiments, the sulfuratom of the thiocycloalkyl group is substituted by one or two oxygenatoms (i.e., a cyclic sulfone or sulfoxide). Exemplary thiocycloalkylgroups include thietanyl, thiolanyl, thianyl, 1,1-dioxothiolanyl, and1,1-dioxothianyl.

Heterocyclyl, unless otherwise specifically defined, referes to a singlesaturated or partially unsaturated 4 to 8 membered ring that has atleast one atom other than carbon in the ring, wherein the atom isselected from the group consisting of oxygen, nitrogen and sulfur; theterm also includes multiple condensed ring systems that have at leastone such saturated or partially unsaturated ring, which multiplecondensed ring systems have from 7 to 12 atoms and are further describedbelow. Thus, the term includes single saturated or partially unsaturatedrings (e.g., 3, 4, 5, 6, 7 or 8 membered rings) from about 1 to 7 carbonatoms and from about 1 to 4 heteroatoms selected from the groupconsisting of oxygen, nitrogen and sulfur in the ring. The ring may beC-branched (i.e., substituted by C₁-C₄ alkyl). The ring may besubstituted with one or more (e.g., 1, 2 or 3) oxo groups and the sulfurand nitrogen atoms may also be present in their oxidized forms.Exemplary heterocycles include but are not limited to azetidinyl,tetrahydrofuranyl and piperidinyl. The rings of the multiple condensedring system can be connected to each other via fused, spiro and bridgedbonds when allowed by valency requirements. It is to be understood thatthe individual rings of the multiple condensed ring system may beconnected in any order relative to one another. It is also to beunderstood that the point of attachment of a multiple condensed ringsystem (as defined above for a heterocycle) can be at any position ofthe multiple condensed ring system. It is also to be understood that thepoint of attachment for a heterocycle or heterocycle multiple condensedring system can be at any suitable atom of the heterocyclyl groupincluding a carbon atom and a nitrogen atom. Exemplary heterocyclesinclude, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl,dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one,2-oxa-6-azaspiro [3,3]heptanyl, imidazolidin-2-one N-methylpiperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran,3-pyrroline, thiopyran, pyrone, tetrhydrothiophene, quinuclidine,tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane,(1s,4s)-2-azabicyclo[2.2.2]octane,(1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one.

In some embodiments, the heterocyclyl is a C₄-C₁₀ heterocyclyl having 1to 3 heteroatoms selected from the group consisting of nitrogen, oxygenand sulfur. In some embodiments, the heterocyclyl group is neitherbicyclic nor spirocyclic. In some embodiments, the heterocyclyl is aC₅-C₆ heterocylcyl having 1 to 3 heteroatoms, wherein at least 2 arenitrogen if 3 heteroatoms are present.

Aryl, unless otherwise specifically defined, refers to a single allcarbon aromatic ring or a multiple condensed all carbon ring systemwherein at least one of the rings is aromatic and wherein the aryl grouphas 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or6 to 10 carbon atoms. Aryl includes a phenyl radical. Aryl also includesmultiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4rings) having about 9 to 20 carbon atoms in which at least one ring isaromatic and wherein the other rings may be aromatic or not aromatic(i.e., carbocycle). Such multiple condensed ring systems are optionallysubstituted with one or more (e.g., 1, 2 or 3) oxo groups on anycarbocycle portion of the multiple condensed ring system. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the point of attachment of a multiple condensedring system, as defined above, can be at any position of the ring systemincluding an aromatic or a carbocycle portion of the ring. Exemplaryaryl groups include phenyl, indenyl, naphthyl, 1, 2, 3,4-tetrahydronaphthyl, anthracenyl, and the like.

Heteroaryl, unless otherwise specifically defined, refers to a 5 to 6membered aromatic ring that has at least one atom other than carbon inthe ring, wherein the atom is selected from the group consisting ofoxygen, nitrogen and sulfur; “heteroaryl” also includes multiplecondensed ring systems having 8 to 16 atoms that have at least one sucharomatic ring, which multiple condensed ring systems are furtherdescribed below. Thus, “heteroaryl” includes single aromatic rings offrom about 1 to 6 carbon atoms and about 1-4 heteroatoms selected fromthe group consisting of oxygen, nitrogen and sulfur. The sulfur andnitrogen atoms may also be present in an oxidized form provided the ringis aromatic. Exemplary heteroaryl ring systems include but are notlimited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” alsoincludes multiple condensed ring systems (e.g., ring systems comprising2 or 3 rings) wherein a heteroaryl group, as defined above, is condensedwith one or more rings selected from heteroaryls (to form for example anaphthyridinyl such as 1,8-naphthyridinyl), heterocycles, (to form forexample a 1, 2, 3, 4-tetrahydronaphthyridinyl such as1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) toform the multiple condensed ring system. Thus, a heteroaryl (a singlearomatic ring or multiple condensed ring system) has 1 to 15 carbonatoms and about 1-6 heteroatoms within the heteroaryl ring. Suchmultiple condensed ring systems may be optionally substituted with oneor more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycleportions of the condensed ring. The rings of the multiple condensed ringsystem can be connected to each other via fused, spiro and bridged bondswhen allowed by valency requirements. It is to be understood that theindividual rings of the multiple condensed ring system may be connectedin any order relative to one another. It is also to be understood thatthe point of attachment of a multiple condensed ring system (as definedabove for a heteroaryl) can be at any position of the multiple condensedring system including a heteroaryl, heterocycle, aryl or carbocycleportion of the multiple condensed ring system. It is also to beunderstood that the point of attachment for a heteroaryl or heteroarylmultiple condensed ring system can be at any suitable atom of theheteroaryl or heteroaryl multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroarylsinclude but are not limited to pyridyl, pyrrolyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl,quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl,quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl,benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl,quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclo-penta[1,2-c]pyrazole.

As used herein, the term “chiral” refers to molecules which have theproperty of non-superimposability of the mirror image partner, while theterm “achiral” refers to molecules which are superimposable on theirmirror image partner.

As used herein, the term “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicates the point ofattachment of the bond that the wavy bond intersects in the chemicalstructure to the remainder of a molecule.

As used herein, the term “C-linked” means that the group that the termdescribes is attached the remainder of the molecule through a ringcarbon atom.

As used herein, the term “N-linked” means that the group that the termdescribes is attached to the remainder of the molecule through a ringnitrogen atom.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers can separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention can contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or l meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer can also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which canoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

When a bond in a compound formula herein is drawn in anon-stereochemical manner (e.g. flat), the atom to which the bond isattached includes all stereochemical possibilities. When a bond in acompound formula herein is drawn in a defined stereochemical manner(e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understoodthat the atom to which the stereochemical bond is attached is enrichedin the absolute stereoisomer depicted unless otherwise noted. In oneembodiment, the compound may be at least 51% the absolute stereoisomerdepicted. In another embodiment, the compound may be at least 80% theabsolute stereoisomer depicted. In another embodiment, the compound maybe at least 90% the absolute stereoisomer depicted. In anotherembodiment, the compound may be at least 95% the absolute stereoisomerdepicted. In another embodiment, the compound may be at least 97% theabsolute stereoisomer depicted. In another embodiment, the compound maybe at least 98% the absolute stereoisomer depicted. In anotherembodiment, the compound may be at least 99% the absolute stereoisomerdepicted.

As used herein, the term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

As used herein, the term “solvate” refers to an association or complexof one or more solvent molecules and a compound of the invention.Examples of solvents that form solvates include, but are not limited to,water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,and ethanolamine. The term “hydrate” refers to the complex where thesolvent molecule is water.

As used herein, the term “protecting group” refers to a substituent thatis commonly employed to block or protect a particular functional groupon a compound. For example, an “amino-protecting group” is a substituentattached to an amino group that blocks or protects the aminofunctionality in the compound. Suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitable protectinggroups include acetyl and silyl. A “carboxy-protecting group” refers toa substituent of the carboxy group that blocks or protects the carboxyfunctionality. Common carboxy-protecting groups includephenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups inOrganic Synthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

As used herein, the term “mammal” includes, but is not limited to,humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows,pigs, and sheep.

As used herein, the term “pharmaceutically acceptable salts” is meant toinclude salts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methane sulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al., “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. As used herein the term “prodrug” refers tothose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs of the invention include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues, is covalently joined through an amide orester bond to a free amino, hydroxy or carboxylic acid group of acompound of the present invention. The amino acid residues include butare not limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes phosphoserine,phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine,demosine, isodemosine, gamma-carboxyglutamate, hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, citrulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁₋₆)alkanoyloxymethyl,1-((C₁₋₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁₋₆)alkanoyloxy)ethyl,(C₁₋₆)alkoxycarbonyloxymethyl, N—(C₁₋₆)alkoxycarbonylaminomethyl,succinoyl, (C₁₋₆)alkanoyl, alpha-amino(C₁₋₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Additionally, the present invention provides for metabolites ofcompounds of the invention. As used herein, a “metabolite” refers to aproduct produced through metabolism in the body of a specified compoundor salt thereof. Such products can result for example from theoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention can exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention.

The term “composition,” as used herein, is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “treat” and “treatment” refer to both therapeutic treatmentand/or prophylactic treatment or preventative measures, wherein theobject is to prevent or slow down (lessen) an undesired physiologicalchange or disorder, such as, for example, the development or spread ofcancer. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease or disorder, stabilized (i.e., notworsening) state of disease or disorder, delay or slowing of diseaseprogression, amelioration or palliation of the disease state ordisorder, and remission (whether partial or total), whether detectableor undetectable. “Treatment” can also mean prolonging survival ascompared to expected survival if not receiving treatment. Those in needof treatment include those already with the disease or disorder as wellas those prone to have the disease or disorder or those in which thedisease or disorder is to be prevented.

The phrase “therapeutically effective amount” or “effective amount”means an amount of a compound of the present invention that (i) beats orprevents the particular disease, condition, or disorder, (ii)attenuates, ameliorates, or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, condition,or disorder described herein. For cancer therapy, efficacy can, forexample, be measured by assessing the time to disease progression (TTP)and/or determining the response rate (RR).

The term “bioavailability” refers to the systemic availability (i.e.,blood/plasma levels) of a given amount of drug administered to apatient. Bioavailability is an absolute term that indicates measurementof both the time (rate) and total amount (extent) of drug that reachesthe general circulation from an administered dosage form.

Inhibitors of RIP1 Kinase

The present invention provides novel compounds having the generalformula I:

or pharmaceutically acceptable salts thereof, whereinR¹ and R²:

-   -   (a) are each independently selected from the group consisting of        C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,        C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, C₁-C₆ alkyl-N(R^(N))₂,        phenyl, 5 to 6 membered heteroaryl, and 4 to 5 membered        heterocyclyl;    -   (b) together with the adjacent amide N, form a 4 to 7 membered        unsaturated heterocyclic ring optionally substituted by one or        two R³, wherein the unsaturated heterocyclic ring contains zero        or one additional heteroatom selected from the group consisting        of NR^(N), O and S; or    -   (c) together with the adjacent amide N, form a bicyclic        heteroaryl moiety optionally substituted by one or two R³,        wherein the bicyclic heterocyclic moiety contains zero to three        additional heteroatoms selected from the group consisting of N,        O and S, wherein only one of the additional heteroatoms is O or        S;        each R³ is independently selected from the group consisting of        F, Cl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl, and phenoxy; or,        when R¹ and R² together with the adjacent amide N form a 6        membered ring, two R³ may together form a 1 to 2 carbon bridge        or a C₃-C₅ spirocycloalkyl;        each R^(N) is independently selected from the group consisting        of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy and C₁-C₆        haloalkyl; or two R^(N) may together with the adjacent N form a        4-6 membered ring;        the A ring is a 5 or 6 membered heteroaryl having 1 to 3        heteroatoms selected from the group consisting of nitrogen,        oxygen and sulfur; wherein the A ring is optionally substituted        with 1 to 2 substituents selected from the group consisting of        halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy and C₁-C₆ haloalkoxy; and wherein if a nitrogen atom in        the A ring is substituted, the substituent is not halogen, C₁-C₆        alkoxy or C₁-C₆ haloalkoxy having an oxygen or sulfur atom        directly bonded to the nitrogen atom;        the B ring is a 5 to 7 membered cycloalkyl, or a 5 to 7 membered        heterocyclyl having 1 to 3 heteroatoms selected from the group        consisting of nitrogen, oxygen and sulfur; wherein the B ring is        substituted according to (a), (b), or both (a) and (b):    -   (a) 1 to 2 substituents selected from the group consisting of        halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, C₁-C₆        alkyl-N(R^(N))₂, and cyano; wherein if a nitrogen atom in the B        ring is substituted, the substituent is not halogen, cyano, or a        C₁-C₆ alkoxy, C₁-C₆ haloalkoxy or C₁-C₆ thioalkyl having an        oxygen or sulfur atom directly bonded to the nitrogen atom;        wherein two substituents on the B ring together may form a 1 to        2 carbon bridge or C₃-C₅ spirocycloalkyl group;    -   (b) 1 substituent selected from the group consisting of phenyl,        benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl),        CH₂-(4 to 6 membered heterocyclyl), CH₂CH₂-(4 to 6 membered        heterocyclyl), 5 or 6 membered heteroaryl, and CH₂-(5 or 6        membered heteroaryl); wherein when a phenyl ring is present it        may be substituted by 1 or 2 substituents selected from the        group consisting of halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄        alkoxy, C₁-C₄ haloalkoxy, and cyano;        provided that if the B ring is substituted by only one        substituent, it is not halogen or methyl.

Also provided herein are compounds of formula I, or pharmaceuticallyacceptable salts thereof, wherein

R¹ and R²:

-   -   (a) are each independently selected from the group consisting of        C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,        C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, C₁-C₆ alkyl-N(R^(N))₂; or    -   (b) together with the adjacent amide N, form a 4 to 6 membered        unsaturated heterocyclic ring optionally substituted by one or        two R³, containing zero or one additional heteroatom selected        from the group consisting of O and S;        each R³ is independently selected from the group consisting of        F, Cl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy and C₁-C₆ haloalkoxy; or, when R¹ and R² together with        the adjacent amide N form a 6 membered ring, two R³ may together        form a 1 to 2 carbon bridge or a C₃-C₅ spirocycloalkyl;        each R^(N) is independently selected from the group consisting        of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy and C₁-C₆        haloalkyl; or two R^(N) may together with the adjacent N form a        4-6 membered ring;        the A ring is a 5 or 6 membered heteroaryl having 1 to 3        heteroatoms selected from the group consisting of nitrogen,        oxygen and sulfur; wherein the A ring is optionally substituted        with 1 to 2 substituents selected from the group consisting of        halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy and C₁-C₆ haloalkoxy; and wherein if a nitrogen atom in        the A ring is substituted, the substituent is not halogen, C₁-C₆        alkoxy or C₁-C₆ haloalkoxy having an oxygen or sulfur atom        directly bonded to the nitrogen atom;        the B ring is a 5 to 7 membered cycloalkyl, or a 5 to 7 membered        heterocyclyl having 1 to 3 heteroatoms selected from the group        consisting of nitrogen, oxygen and sulfur; wherein the B ring is        substituted according to (a), (b), or both (a) and (b):    -   (a) 1 to 2 substituents selected from the group consisting of        halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkyl, C₁-C₆        alkyl-N(R^(N))₂, and cyano; wherein if a nitrogen atom in the B        ring is substituted, the substituent is not halogen, cyano, or a        C₁-C₆ alkoxy, C₁-C₆ haloalkoxy or C₁-C₆ thioalkyl having an        oxygen or sulfur atom directly bonded to the nitrogen atom;        wherein two substituents on the B ring together may form a 1 to        2 carbon bridge or C₃-C₅ spirocycloalkyl group;    -   (b) 1 substituent selected from the group consisting of phenyl,        benzyl, CH₂—(C₃-C₆ cycloalkyl), and CH₂CH₂—(C₃-C₆ cycloalkyl),        CH₂-(4 to 6 membered heterocyclyl), CH₂CH₂-(4 to 6 membered        heterocyclyl), 5 or 6 membered heteroaryl, and CH₂-(5 or 6        membered heteroaryl); wherein when a phenyl ring is present it        may be substituted by 1 or 2 substituents selected from the        group consisting of halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄        alkoxy, C₁-C₄ haloalkoxy, and cyano;        provided that if the B ring is substituted by only one        substituent, it is not halogen or methyl.

In some embodiments, R¹ and R² are each independently selected from thegroup consisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, C₁-C₆ alkyl-N(R^(N))₂. In some embodiments, R¹ and R² areeach a C₁-C₆ alkyl. In some embodiments, R¹ and R² are each methyl.

In some embodiments, R¹ is selected from the group consisting of C₁-C₃alkyl, C₃-C₅ cycloalkyl, and C₁-C₃ haloalkyl; and R² is selected fromthe group consisting of C₁-C₃ alkyl, C₃-C₅ cycloalkyl, C₁-C₄ alkoxy,phenyl, and 4 to 5 membered heterocyclyl.

In some embodiments, wherein R¹ is selected from the group consisting ofmethyl, cyclopropyl, —CH₂CF₂H and —CH₂CF₃; and R² is selected from thegroup consisting of methyl, cyclopropyl, —CH₂CH₂OCH₃, phenyl, andoxetan-3-yl.

In some embodiments, each R^(N) is independently selected from the groupconsisting of H and C₁-C₆ alkyl. In some embodiments, each R^(N) is aC₁-C₄ alkyl. In some embodiments, each R^(N) is methyl.

Also provided herein are compounds of Formula (Ia):

wherein R³, ring A and ring B are as defined herein; m is 0, 1 or 2; andn is 1, 2 or 3.

In some embodiments of Formula (Ia), m is 0. In some embodiments, m is 1and each R³ is selected from the group consisting of F, Cl, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆ haloalkoxy. In some embodiments,m is 2 and each R³ is selected from the group consisting of F, C₁-C₆alkyl, and C₁-C₆ haloalkyl. In some embodiments, m is 2 and each R³ isF.

In some embodiments of Formula (Ia), each R³ is selected from the groupconsisting of methyl, ethyl, F and Cl. In some embodiments, each R³ ismethyl or F.

In some embodiments, n is 1. In some embodiments, n is 2. In someembodiments, n is 3.

In some embodiments of Formula (Ia),

is selected from the group consisting of:

In some embodiments of Formula (Ia),

is selected from the group consisting of:

In some embodiments of Formula (Ia),

is selected from the group consisting of:

Also provided herein are compounds of Formula (Ib) or (Ic):

wherein, in each instance,the C ring is phenyl or a 5 to 6 membered heteroaryl ring;

Z is C or N;

each R³ is independently selected from the group consisting of F, Cl,C₁-C₃ alkyl, C₃-C₅ cycloalkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, and C₁-C₃haloalkoxy;n is 1 or 2; andm is 0, 1 or 2.

In some embodiments of Formulae (Ib) or (Ic), each R³ is independentlyselected from the group consisting of F and C₁-C₃ alkyl.

In some embodiments of Formulae (Ib) or (Ic),

are selected from the group consisting of:

In some embodiments,

is selected from the group consisting of:

whereinX¹, X⁴, X⁵ are each selected from the group consisting of NR⁷ and CR⁸;X² and X³ are each selected from the group consisting of N or C;Y¹ and Y² are each selected from the group consisting of O, S, SO, SO₂,and CR^(6a)R^(6b);R⁴ is selected from the group consisting of phenyl and 5 to 6 memberedheteroaryl, wherein the heteroaryl has one or two heteroatoms selectedfrom O, S and N, and phenyl may be substituted by 1 or 2 substituentsselected from the group consisting of halogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;each R^(5a) and R^(5b) is independently selected from the groupconsisting of H, F, Cl, C₁-C₆ alkyl, C₃-C₄ cycloalkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy; wherein R^(5a) and R^(5b) together withthe carbon to which they are attached may form a 3 or 4 memberedcycloalkyl optionally substituted by one or two F, or a 4 memberedcycloalkoxy;each R^(6a) and R^(6b) is independently selected from the groupconsisting of H, F, Cl, and C₁-C₄ alkyl;each R⁷ is independently selected from the group consisting of H andC₁-C₄ alkyl;each R⁸ is independently selected from the group consisting of H, halo,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and C₁-C₄ haloalkoxy;provided that only one of X² and X³ is N, and the ring comprising X¹-X⁴or X¹-X⁵ has 1, 2 or 3 nitrogen atoms;further provided that one of Y¹ or Y² is CR^(6a)R^(6b).

In some embodiments,

is selected from the group consisting of:

whereinX¹, X⁴, X⁵ are each selected from the group consisting of NR⁷ and CR⁸;X² and X³ are each selected from the group consisting of N or C;Y¹ and Y² are each selected from the group consisting of O, S, SO, SO₂,and CR^(6a)R^(6b);R⁴ is selected from the group consisting of phenyl and 5 to 6 memberedheteroaryl, wherein the heteroaryl has one or two heteroatoms selectedfrom O, S and N, and phenyl may be substituted by 1 or 2 substituentsselected from the group consisting of halogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;each R^(5a) and R^(5b) is independently selected from the groupconsisting of H, F, Cl, C₁-C₆ alkyl, C₃-C₄ cycloalkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy; wherein R^(5a) and R^(5b) together withthe carbon to which they are attached may form a 3 or 4 memberedcycloalkyl optionally substituted by one or two F, or a 4 memberedcycloalkoxy;each R^(6a) and R^(6b) is independently selected from the groupconsisting of H, F, Cl, and C₁-C₄ alkyl;each R⁷ is independently selected from the group consisting of H andC₁-C₄ alkyl;each R⁸ is independently selected from the group consisting of H, halo,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and C₁-C₄ haloalkoxy;provided that only one of X² and X³ is N, and the ring comprising X¹-X⁴or X¹-X⁵ has 1, 2 or 3 nitrogen atoms;further provided that one of Y¹ or Y² is CR^(6a)R^(6b).

In some embodiments, R⁴ is phenyl. In some embodiments, R⁴ is mono- ordifluorophenyl.

In some embodiments, each R^(5a) and R^(5b) is independently selectedfrom the group consisting of H, C₁-C₆ alkyl, C₃-C₄ cycloalkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy; wherein R^(5a) and R^(5b)together with the carbon to which they are attached may form a 3 or 4membered cycloalkyl optionally substituted by one or two F, or a 4membered cycloalkoxy.

In some embodiments, R^(5a) and R^(5b) are each independently H or F. Insome embodiments, R^(5a) and R^(5b) are each independently H or F; andR^(6a) and R^(6b) are each H. In some embodiments, R^(5a), R^(5b),R^(6a), and R^(6b) are each H. In some embodiments, R^(5a) and R^(5b)are each F.

In some embodiments, each R^(6a) and R^(6b) is independently selectedfrom the group consisting of H and C₁-C₄ alkyl. In some embodiments,R^(6a) and R^(6b) are each H.

In some embodiments, Y¹ and Y² are each CR^(6a)R^(6b). In someembodiments, Y¹ is CH₂ and Y² is CR^(6a)R^(6b). In some embodiments, Y¹is CR^(6a)R^(6b) and Y² is CH₂. In some embodiments, Y¹ and Y² are eachCH₂. In some embodiments, Y¹ is O and Y² is CR^(6a)R^(6b). In someembodiments, Y¹ is CR^(6a)R^(6b) and Y² is O. In some embodiments, Y¹ isO and Y² is CH₂. In some embodiments, Y¹ is CH₂ and Y² is O.

In some embodiments, each R⁷ is independently selected from the groupconsisting of H and methyl. In some embodiments, each R⁷ is H.

In some embodiments, each R⁸ is H.

In some embodiments,

-   -   X¹, X⁴, X⁵ are each selected from the group consisting of NR⁷        and CR⁸;    -   X² and X³ are each selected from the group consisting of N or C;    -   Y¹ and Y² are each selected from the group consisting of O and        CR^(6a)R^(6b); and    -   each of R^(6a), R^(6b), R⁷ and R⁸ are as defined above;    -   provided that only one of X² and X³ is N, and the ring        comprising X¹-X⁴ or X¹-X⁵ has 1 or 2 nitrogen atoms;    -   further provided that one of Y¹ or Y² is CR^(6a)R^(6b).

In some embodiments,

is selected from the group consisting of:

whereinX¹, X², X³, X⁴, X⁵, R⁴, R^(5a), R^(5b), R^(6a) and R^(6b) are as definedabove.

In some embodiments,

is selected from the group consisting of:

In some embodiments,

is selected from the group consisting of:

Also provided herein are embodiments corresponding to each of thosedescribed above, wherein each substituent is unsubstituted unlessexplicitly provided in the embodiment.

In another embodiment, provided herein is a compound selected from thecompounds of Table 1 below. In another embodiment, provided herein is acompound selected from the compounds of Table 2 below.

Also provided herein is a method for the treatment or prophylaxis of adisease or disorder in a human, the method comprising administration tothe human of an effective amount of a compound provided herein, whereinthe disease or disorder is selected from the group consisting ofirritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn'sdisease, ulcerative colitis, myocardial infarction, stroke, traumaticbrain injury, atherosclerosis, ischemia-reperfusion injury of kidneys,liver and lungs, cisplatin-induced kidney injury, sepsis, systemicinflammatory response syndrome (SIRS), pancreatits, psoriasis, retinitispigmentosa, retinal degeneration, chronic kidney diseases, acuterespiratory distress syndrome (ARDS), chronic obstructive pulmonarydisease (COPD).

Also provided herein is a method for the treatment of a disease ordisorder in a human, the method comprising administration to the humanof an effective treatment amount of a compound provided herein, whereinthe disease or disorder is selected from the group consisting ofirritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn'sdisease, ulcerative colitis, myocardial infarction, stroke, traumaticbrain injury, atherosclerosis, ischemia-reperfusion injury of kidneys,liver and lungs, cisplatin-induced kidney injury, sepsis, systemicinflammatory response syndrome (SIRS), pancreatits, psoriasis, retinitispigmentosa, retinal degeneration, chronic kidney diseases, acuterespiratory distress syndrome (ARDS), chronic obstructive pulmonarydisease (COPD).

Pharmaceutical Compositions and Administration

Provided herein are pharmaceutical compositions or medicamentscontaining the compounds of the invention (or stereoisomers, geometricisomers, tautomers, solvates, metabolites, isotopes, pharmaceuticallyacceptable salts, or prodrugs thereof), and a therapeutically inertcarrier, diluent or excipient, as well as methods of using the compoundsof the invention to prepare such compositions and medicaments. In oneexample, compounds of formula I may be formulated by mixing at ambienttemperature at the appropriate pH, and at the desired degree of purity,with physiologically acceptable carriers, i.e., carriers that arenon-toxic to recipients at the dosages and concentrations employed intoa galenical administration form. The pH of the formulation dependsmainly on the particular use and the concentration of compound, butpreferably ranges anywhere from about 3 to about 8. In one example, acompound of formula I is formulated in an acetate buffer, at pH 5. Inanother embodiment, the compounds of formula I are sterile. The compoundmay be stored, for example, as a solid or amorphous composition, as alyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. In some embodiments, the “effectiveamount” of the compound to be administered will be governed by suchconsiderations, and is the minimum amount necessary to inhibit RIP1kinase activity in order to provide a therapeutic effect in the mammalbeing treated. In addition, such an effective amount may be below theamount that is toxic to normal cells, or the mammal as a whole.

In one example, the pharmaceutically effective amount of the compound ofthe invention administered intravenously or parenterally will be in theper dose range of about 0.1 to 100 mg/kg, alternatively about 0.1 to 20mg/kg of patient body weight per day, or alternatively about 0.3 to 15mg/kg/day.

In another embodiment, oral unit dosage forms, such as tablets andcapsules, preferably contain from about 1 to about 1000 mg (e.g., 1 mg,5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 100 mg, 200 mg,250 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg) ofthe compound of the invention. The daily does is, in certainembodiments, given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. In the case of a 70 kg adulthuman, the total daily dose will generally be from about 7 mg to about1,400 mg. This dosage regimen may be adjusted to provide the optimaltherapeutic response. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

In some embodiments, a low dose of the compound of the invention isadministered in order to provide therapeutic benefit while minimizing orpreventing adverse effects.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration. In specificembodiments, the compound of formula I is administered orally. In otherspecific embodiments, the compound of formula I is administeredintravenously.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Formsand Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al.

Remington: The Science and Practice of Pharmacy. Philadelphia:Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook ofPharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents, diluents and other known additives to provide an elegantpresentation of the drug (i.e., a compound of the present invention orpharmaceutical composition thereof) or aid in the manufacturing of thepharmaceutical product (i.e., medicament).

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water and the like. The particularcarrier, diluent or excipient used will depend upon the means andpurpose for which a compound of the present invention is being applied.Solvents are generally selected based on solvents recognized by personsskilled in the art as safe (GRAS) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations can also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Aactive pharmaceutical ingredient of the invention (e.g., compound offormula I or an embodiment thereof) can also be entrapped inmicrocapsules prepared, for example, by coacervation techniques or byinterfacial polymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philadelphia, Pa.

Sustained-release preparations of a compound of the invention (e.g.,compound of formula I or an embodiment thereof) can be prepared.Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of formula I or an embodiment thereof, which matrices are inthe form of shaped articles, e.g., films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983),non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater.Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers suchas the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate) andpoly-D-(−)-3-hydroxybutyric acid (EP 133,988A). Sustained releasecompositions also include liposomally entrapped compounds, which can beprepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci.U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A.77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A).Ordinarily, the liposomes are of the small (about 200-800 Angstroms)unilamellar type in which the lipid content is greater than about 30 mol% cholesterol, the selected proportion being adjusted for the optimaltherapy.

In one example, compounds of formula I or an embodiment thereof may beformulated by mixing at ambient temperature at the appropriate pH, andat the desired degree of purity, with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed into a galenical administration form. The pHof the formulation depends mainly on the particular use and theconcentration of compound, but preferably ranges anywhere from about 3to about 8. In one example, a compound of formula I (or an embodimentthereof) is formulated in an acetate buffer, at pH 5. In anotherembodiment, the compounds of formula I or an embodiment thereof aresterile. The compound may be stored, for example, as a solid oramorphous composition, as a lyophilized formulation or as an aqueoussolution.

An example of a suitable oral dosage form provided herein is a tabletcontaining about 1 to about 500 mg (e.g., about 1 mg, 5 mg, 10 mg, 25mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg) ofthe compound of the invention compounded with suitable amounts ofanhydrous lactose, sodium croscarmellose, polyvinylpyrrolidone (PVP)K30, and magnesium stearate.

The powdered ingredients are first mixed together and then mixed with asolution of the PVP. The resulting composition can be dried, granulated,mixed with the magnesium stearate and compressed to tablet form usingconventional equipment.

Formulations of a compound of the invention (e.g., compound of formula Ior an embodiment thereof) can be in the form of a sterile injectablepreparation, such as a sterile injectable aqueous or oleaginoussuspension. This suspension can be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, such as a solution in1,3-butanediol or prepared as a lyophilized powder. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile fixed oilscan conventionally be employed as a solvent or suspending medium. Forthis purpose any bland fixed oil can be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid canlikewise be used in the preparation of injectables.

The amount of active ingredient that can be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans cancontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which can varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion can contain from about 3 to 500 jxg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which can contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which can include suspending agents and thickeningagents.

The formulations can be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described.

An embodiment, therefore, includes a pharmaceutical compositioncomprising a compound of formula I, or pharmaceutically acceptable saltthereof. In a further embodiment includes a pharmaceutical compositioncomprising a compound of formula I, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier orexcipient.

When the binding target is located in the brain, certain embodiments ofthe invention provide for a compound of formula I (or an embodimentthereof) to traverse the blood-brain barrier. In these embodiments, thecompounds provided herein exhibit sufficient brain penetration aspotential therapeutics in neurological diseases. In some embodiments,brain penetration is assessed by evaluating free brain/plasma ratio(B_(u)/P_(u)) as measured in vivo pharmacokinetic studies in rodents orby other methods known to persons skilled in the art (see, e.g., Liu, X.et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008).

Certain neurological diseases are associated with an increase inpermeability of the blood-brain barrier, such that a compound of formulaI (or an embodiment thereof) can be readily introduced to the brain.When the blood-brain barrier remains intact, several art-knownapproaches exist for transporting molecules across it, including, butnot limited to, physical methods, lipid-based methods, and receptor andchannel-based methods. Physical methods of transporting a compound offormula I (or an embodiment thereof) across the blood-brain barrierinclude, but are not limited to, circumventing the blood-brain barrierentirely, or by creating openings in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injectioninto the brain (see, e.g., Papanastassiou et al., Gene Therapy9:398-406, 2002), interstitial infusion/convection-enhanced delivery(see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91:2076-2080,1994), and implanting a delivery device in the brain (see, e.g., Gill etal., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford.

Methods of creating openings in the barrier include, but are not limitedto, ultrasound (see, e.g., U.S. Patent Publication No. 2002/0038086),osmotic pressure (e.g., by administration of hypertonic mannitol(Neuwelt, E. A., Implication of the Blood-Brain Barrier and itsManipulation, Volumes 1 and 2, Plenum Press, N.Y., 1989)), andpermeabilization by, e.g., bradykinin or permeabilizer A-7 (see, e.g.,U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

Lipid-based methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, encapsulating the a compound of formula I or I-I (or anembodiment thereof) in liposomes that are coupled to antibody bindingfragments that bind to receptors on the vascular endothelium of theblood-brain barrier (see, e.g., U.S. Patent Publication No.2002/0025313), and coating a compound of formula I (or an embodimentthereof) in low-density lipoprotein particles (see, e.g., U.S. PatentPublication No. 2004/0204354) or apolipoprotein E (see, e.g., U.S.Patent Publication No. 2004/0131692).

Receptor and channel-based methods of transporting a compound of formulaI (or an embodiment thereof) across the blood-brain barrier include, butare not limited to, using glucocorticoid blockers to increasepermeability of the blood-brain barrier (see, e.g., U.S. PatentPublication Nos. 2002/0065259, 2003/0162695, and 2005/0124533);activating potassium channels (see, e.g., U.S. Patent Publication No.2005/0089473), inhibiting ABC drug transporters (see, e.g., U.S. PatentPublication No. 2003/0073713); coating a compound of formula I or I-I(or an embodiment thereof) with a transferrin and modulating activity ofthe one or more transferrin receptors (see, e.g., U.S. PatentPublication No. 2003/0129186), and cationizing the antibodies (see,e.g., U.S. Pat. No. 5,004,697).

For intracerebral use, in certain embodiments, the compounds can beadministered continuously by infusion into the fluid reservoirs of theCNS, although bolus injection may be acceptable. The inhibitors can beadministered into the ventricles of the brain or otherwise introducedinto the CNS or spinal fluid. Administration can be performed by use ofan indwelling catheter and a continuous administration means such as apump, or it can be administered by implantation, e.g., intracerebralimplantation of a sustained-release vehicle. More specifically, theinhibitors can be injected through chronically implanted cannulas orchronically infused with the help of osmotic minipumps. Subcutaneouspumps are available that deliver proteins through a small tubing to thecerebral ventricles. Highly sophisticated pumps can be refilled throughthe skin and their delivery rate can be set without surgicalintervention. Examples of suitable administration protocols and deliverysystems involving a subcutaneous pump device or continuousintracerebroventricular infusion through a totally implanted drugdelivery system are those used for the administration of dopamine,dopamine agonists, and cholinergic agonists to Alzheimer's diseasepatients and animal models for Parkinson's disease, as described byHarbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al.,Mov. Disord. 2: 143, 1987.

Indications and Methods of Treatment

The compounds of the invention inhibit RIP1 kinase activity.Accordingly, the compounds of the invention are useful for the treatmentof diseases and disorders mediated by this pathway and associated withinflammation and/or necroptotic cell death. Compounds of the inventionare therefore useful for the treatment or prevention of a disease ordisorder selected from the group consisting of irritable bowel disorders(IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerativecolitis, myocardial infarction, stroke, traumatic brain injury,atherosclerosis, ischemia-reperfusion injury of kidneys, liver andlungs, cysplatin-induced kidney injury, sepsis, systemic inflammatoryresponse syndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa,retinal degeneration, chronic kidney diseases, acute respiratorydistress syndrome (ARDS), and chronic obstructive pulmonary disease(COPD).

In another embodiment, compounds of the invention are useful for thetreatment of one or more symptoms of the above diseases and disorders.In some embodiments, the disease or disorder is an irritable boweldisorder. In some embodiments, the disease or disorder is irritablebowel syndrome (IBS), Crohn's disease, or ulcerative colitis. In someembodiments, the disease or disorder is an ischemia-reperfusion injuryof kidneys, liver and lungs. In some embodiments, the disease ordisorder is a chronic kidney disease. In some embodiments, the diseaseor disorder is acute respiratory distress syndrome (ARDS). In someembodiments, the disease or disorder is chronic obstructive pulmonarydisease (COPD).

In some embodiments, the disease or disorder to be treated is selectedfrom the group consisting of inflammatory bowel diseases (includingCrohn's disease and ulcerative colitis), psoriasis, retinal detachment,retinitis pigmentosa, macular degeneration, pancreatitis, atopicdermatitis, arthritis (including rheumatoid arthritis, osteoarthritis,spondylarthritis, gout, systemic onset juvenile idiopathic arthritis(SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE),Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome(APS), vasculitis, liver damage/diseases (non-alcohol steatohepatitis,alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliarydiseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity,hepatotoxicity), kidney damage/injury (nephritis, renal transplant,surgery, administration of nephrotoxic drugs e.g. cisplatin, acutekidney injury (AKI)), Celiac disease, autoimmune idiopathicthrombocytopenic purpura, transplant rejection, ischemia reperfusioninjury of solid organs, sepsis, systemic inflammatory response syndrome(SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction(MI), atherosclerosis, Huntington's disease, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinalmuscular atropy (SMA), allergic diseases (including asthma and atopicdermatitis), multiple sclerosis, type I diabetes, Wegener'sgranulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1converting enzyme (ICE, also known as caspase-1) associated feversyndrome, chronic obstructive pulmonary disease (COPD), tumor necrosisfactor receptor-associated periodic syndrome (TRAPS), periodontitis,NEMO-deficiency syndrome (F-kappa-B essential modulator gene (also knownas IKK gamma or IKKG) deficiency syndrome), HOIL-1 deficiency ((alsoknown as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1 deficiency),linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome,hematological and solid organ malignancies, bacterial infections andviral infections (such as tuberculosis and influenza), and Lysosomalstorage diseases (particularly, Gaucher Disease, and including GM2,Gangliosidosis, Alpha-mannosidosis, Aspartylglucosaminuria, CholesterylEster storage disease, Chronic Hexosaminidase A Deficiency, Cystinosis,Danon disease, Fabry disease, Farber disease, Fucosidosis,Galactosialidosis, GM1 gangliosidosis, Mucolipidosis, Infantile FreeSialic Acid Storage Disease, Juvenile Hexosaminidase A Deficiency,Krabbe disease, Lysosomal acid lipase deficiency, MetachromaticLeukodystrophy, Mucopolysaccharidoses disorders, Multiple sulfatasedeficiency, Niemann-Pick Disease, Neuronal Ceroid Lipofuscinoses, Pompedisease, Pycnodysostosis, Sandhoff disease, Schindler disease, SialicAcid Storage Disease, Tay-Sachs and Wolman disease).

Also provided herein is the use of a compound of the invention intherapy. In some embodiments, provided herein is the use of a compoundof the invention for the treatment or prevention of the above diseasesand disorders. Also provided herein is the use of a compound of theinvention in the manufacture of a medicament for the treatment orprevention of the above diseases and disorders.

Also provided herein is a method of treating a disease or disorder in amammal in need of such treatment, said disease or disorder beingselected from the group consisting of irritable bowel disorders (IBD),irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis,myocardial infarction, stroke, traumatic brain injury, atherosclerosis,ischemia-reperfusion injury of kidneys, liver and lungs,cysplatin-induced kidney injury, sepsis, systemic inflammatory responsesyndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa, retinaldegeneration, chronic kidney diseases, acute respiratory distresssyndrome (ARDS), and chronic obstructive pulmonary disease (COPD),wherein the method comprises administering to said mammal atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof.

Also provided herein is a method of treating a symptom of a disease ordisorder in a mammal in need of such treatment, said disease or disorderbeing selected from the group consisting of irritable bowel disorders(IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerativecolitis, myocardial infarction, stroke, traumatic brain injury,atherosclerosis, ischemia-reperfusion injury of kidneys, liver andlungs, cysplatin-induced kidney injury, sepsis, systemic inflammatoryresponse syndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa,retinal degeneration, chronic kidney diseases, acute respiratorydistress syndrome (ARDS), and chronic obstructive pulmonary disease(COPD), wherein the method comprises administering to said mammal atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof.

Also provided herein is a method of treating a disease or disorder in amammal in need of such treatment, said disease or disorder beingselected from the group consisting of irritable bowel disorders (IBD),irritable bowel syndrome (IBS), Crohn's disease, and ulcerative colitis,wherein the method comprises orally administering to said mammal atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, as an orally acceptablepharmaceutical composition.

Combination Therapy

Compounds of the invention may be combined with one or more othercompounds of the invention or one or more other therapeutic agent as anycombination thereof, in the treatment of the diseases and disordersprovided herein. For example, a compound of the invention may beadministered simultaneously, sequentially or separately in combinationwith other therapeutic agents known to be useful for the treatment of adisease or disorder selected from those recited above.

In some embodiments, a compound provided herein may be combined withanother therapeutically active agent as recited in WO 2016/027253, thecontents of which are hereby incorporated by reference in theirentirety. In such embodiments, the compound that inhibits RIP1 kinase inthe combinations recited in WO 2016/027253 is replaced by a compound offormula I of the present disclosure.

As used herein “combination” refers to any mixture or permutation of oneor more compounds of the invention and one or more other compounds ofthe invention or one or more additional therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include simultaneous orsequentially delivery of a compound of the invention with one or moretherapeutic agents. Unless the context makes clear otherwise,“combination” may include dosage forms of a compound of the inventionwith another therapeutic agent. Unless the context makes clearotherwise, “combination” may include routes of administration of acompound of the invention with another therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include formulations ofa compound of the invention with another therapeutic agent. Dosageforms, routes of administration and pharmaceutical compositions include,but are not limited to, those described herein.

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

These examples serve to provide guidance to a skilled artisan to prepareand use the compounds, compositions and methods of the invention. Whileparticular embodiment of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinventions.

The chemical reactions in the examples described can be readily adaptedto prepare a number of other compounds of the invention, and alternativemethods for preparing the compounds of this invention are deemed to bewithin the scope of this invention. For example, the synthesis ofnon-exemplified compounds according to the invention can be successfullyperformed by modifications apparent to those skilled in the art, forexample, by appropriately protecting interfering group, by utilizingother suitable reagents known in the art, for example, by appropriatelyprotecting interfering groups by utilizing other suitable reagents knownin the art other than those described, and/or by making routinemodifications of reaction conditions.

In the examples below, unless otherwise indicated all temperatures areset forth in degrees Celsius. Commercially available reagents werepurchased from suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge and were used without further purification unlessotherwise indicated. The reactions set forth below were done generallyunder a positive pressure of nitrogen or argon or with a drying tube(unless otherwise stated) in anhydrous solvents, and the reaction flaskswere typically fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. ¹H NMR spectra were obtained in deuterated CDCl₃, d₆-DMSO,CH₃OD or d₆-acetone solvent solutions (reported in ppm) using ortrimethylsilane (TMS) or residual non-deuterated solvent peaks as thereference standard. When peak multiplicities are reported, the followingabbreviates are used: s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet, br (broadened), dd (doublet of doublets), dt(doublet of triplets). Coupling constants, when given, ar reported in Hz(Hertz).

In the examples below, LCMS methods were performed for 10 or 30 minutesaccording to the following conditions:

Agilent 10 min LCMS Method: Experiments performed on an Agilent 1290UHPLC coupled with Agilent MSD (6140) mass spectrometer using ESI asionization source. The LC separation was using a Phenomenex XB-C18, 1.7mm, 50×2.1 mm column with a 0.4 ml/minute flow rate. Solvent A is waterwith 0.1% FA and solvent B is acetonitrile with 0.1% FA. The gradientconsisted with 2-98% solvent B over 7 min and hold 98% B for 1.5 minfollowing equilibration for 1.5 min. LC column temperature is 40° C. UVabsorbance was collected at 220 nm and 254 nm and mass spec full scanwas applied to all experiment.

Agilent 30 min LCMS Method: Experiments performed on an Agilent 1100HPLC coupled with Agilent MSD mass spectrometer using ESI as ionizationsource. The LC separation was using an Agilent Eclipse XDB-C18, 3.5 mm,100×3.0 mm column with a 0.7 ml/minute flow rate. Solvent A is waterwith 0.1% FA and solvent B is acetonitrile with 0.1% FA. The gradientconsisted with 2-98% solvent B over 25.5 min and hold 98% B for 2.5 minfollowing equilibration for 1.5 min. UV absorbance were collected at 220nm and 254 nm and mass spec full scan was applied to all experiment.

All abbreviations used to describe reagents, reaction conditions orequipment are intended to be consistent with the definitions set forthin the following list of Abbreviations. The chemical names of discretecompounds of the invention were typically obtained using the structurenaming feature of ChemDraw naming program.

Abbreviations

-   ACN Acetonitrile-   Boc tert-Buloxy carbonyl-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   HPLC High Pressure Liquid Chromatography-   LCMS Liquid Chromatography Mass Spectrometry-   RP Reverse phase-   RT or RT Retention time-   SEM 2-(Trimethylsilyl)ethoxymethyl-   THF Tetrahydrofuran

Example 1: Synthetic Method #1

(3,3-difluoroazetidin-1-yl)-(7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone,(S)-(7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3,3-difluoroazetidin-1-yl)methanoneand(R)-(7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3,3-difluoroazetidin-1-yl)methanone

Step 1: (E)-Benzaldehyde Oxime

To a solution of benzaldehyde (45.0 g, 424.1 mmol) in ethanol (100 mL)was added sodium carbonate (112.3 g, 1060.1 mmol) and hydroxylaminehydrochloride (35.3 g, 508.9 mmol). The reaction mixture was stirred at25° C. for 3 h and filtered. The filtrate was concentrated under reducedpressure and the residue was diluted with water (50 mL). The resultingmixture was extracted with ethyl acetate (3×150 mL). The combinedorganic layers were washed with brine (60 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to afford crude(E)-benzaldehyde oxime as colorless oil (51.0 g, 99%), used in the nextstep without further purification.

Step 2: methyl 3-phenyl-4, 5-dihydroisoxazole-5-carboxylate

To a solution of (E)-benzaldehyde oxime (20.0 g, 165.1 mmol) in1,4-dioxane (500 mL) was added methyl acrylate (14.2 g, 165.1 mmol),sodium iodide (24.7 g, 165.1 mmol), 2,6-lutidine (17.6 g, 165.1 mmol)and hypochlorous acid tert-butyl ester (17.9 g, 165.1 mmol). Thereaction mixture was stirred at 25° C. for 24 h and subsequentlyconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate inpetroleum ether) to afford methyl3-phenyl-4,5-dihydroisoxazole-5-carboxylate as a yellow solid (25.0 g,74%). LCMS R_(T)=0.871 min, m/z=206.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0mins) retention time 0.871 min, ESI+ found [M+H]=206.2.

Step 3: 3-hydroxy-5-phenyl-pyrrolidin-2-one

A mixture of methyl 3-phenyl-4, 5-dihydroisoxazole-5-carboxylate (25.0g, 121.8 mmol) and palladium (10% on carbon, 2.5 g) in ethanol (800 mL)was hydrogenated (50 psi) at 25° C. for 2 h and then filtered and thefiltrate was concentrated under reduced pressure to afford crude3-hydroxy-5-phenyl-pyrrolidin-2-one as a yellow solid (18.0 g, 83%),used in the next step without further purification. LCMS R_(T)=0.270min, m/z=177.8 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.270 min, ESI+ found [M+H]=177.8.

Step 4: cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one &trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one

To a solution of 3-hydroxy-5-phenyl-pyrrolidin-2-one (15.0 g, 84.6 mmol)in dichloromethane (300 mL) was added tert-butyldimethylchlorosilane(19.1 g, 126.9 mmol) and imidazole (11.5 g, 169.3 mmol). The reactionmixture was stirred at 25° C. for 16 h and subsequently concentratedunder reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate inpetroleum ether) to afford

cis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (12.4 g,51%). ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.25 (m, 5H), 4.88-4.53 (m, 1H),4.54-4.46 (m, 1H), 2.89-2.79 (m, 1H), 1.80-1.71 (m, 1H), 0.93-0.90 (m,9H), 0.19-0.12 (m, 6H) and

trans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one as acolorless oil (9.3 g, 38%). ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.34 (m, 2H),7.29-7.24 (m, 3H), 4.87-4.80 (m, 1H), 4.44-4.41 (m, 1H), 2.45-2.37 (m,1H), 2.27-2.22 (m, 1H), 0.93-0.90 (m, 9H), 0.16-0.13 (m, 6H).

Step 5:cis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one

To a solution ofcis-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (12.4 g,42.8 mmol) in N,N-dimethylformamide (400 mL) was slowly added sodiumhydride (60%, 2.6 g, 64.1 mmol) at 0° C. After addition, the mixture wasstirred at 0° C. for 20 min and subsequentlyO-(diphenylphosphoryl)hydroxylamine (14.9 g, 64.1 mmol) was added. Thereaction mixture was stirred at 25° C. for 16 h and then filtered. Thefiltrate was concentrated under reduced pressure to afford the crudecis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-oneas a yellow oil (9.5 g, 73%), used in the next step without furtherpurification. LCMS R_(T)=0.877 min, m/z=307.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.877 min, ESI+ found [M+H]=307.0.

Step 6: ethyl2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate

To a solution ofcis-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one(9.5 g, 31.0 mmol) in ethanol (250 mL) was added ethyl2-ethoxy-2-imino-acetate (6.7 g, 46.5 mmol). The reaction mixture wasstirred at 60° C. for 6 h and subsequently concentrated under reducedpressure to afford crude ethyl2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetateas a yellow oil (10.6 g, 84%), used in the next step without furtherpurification. LCMS R_(T)=2.106 min, m/z=406.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.1% ammonia water over 3.0 mins)retention time 2.106 min, ESI+ found [M+H]=406.2.

Step 7: ethylcis-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate(10.6 g, 26.1 mmol) in toluene (200 mL) was added p-toluenesulfonic acid(4.5 g, 26.1 mmol). The reaction mixture was heated at 120° C. for 24 hand subsequently concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 100-200 mesh, 0 to 80%ethyl acetate in petroleum ether) to afford ethylcis-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylateas a white solid (6.5 g, 64%), used as is in the next step.

Step 8: ethylcis-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of ethyl2-[[cis-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate(3.1 g, 7.6 mmol) and tert-butylammonium fluoride (1.0 M in THF, 7.6 mL,7.6 mmol) in tetrahydrofuran (60 mL) was heated at 60° C. for 18 h andsubsequently concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 100-200 mesh, 0 to 100%ethyl acetate in petroleum ether) to give ethylcis-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylateas white solid (1.4 g, 69%). ¹H NMR (400 MHz, CDCl₃) δ7.39-7.32 (m, 5H),5.73 (d, J=3.5 Hz, 1H), 5.50 (m, 1H), 4.41 (q, J=7.1 Hz, 2H), 3.73-3.65(m, 1H), 2.76 (td, J=4.5 Hz, 13.9 Hz, 1H), 1.35 (t, J=7.1 Hz, 3H).

Step 9: ethyl7-oxo-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution ofcis-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(1.0 g, 3.6 mmol) in dichloromethane (100 mL) was added manganesedioxide (0.9 g, 10.9 mmol). The mixture was heated at reflux for 3 h andsubsequently filtered. The filtrate was concentrated under reducedpressure and the residue was purified by column chromatography (silicagel, 100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to affordethyl7-oxo-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(350 mg, 35%) as a pink solid. LCMS R_(T)=0.725 min, m/z=271.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.725 min, ESI+ found [M+H]=271.9.

Step 10: ethyl7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl7-oxo-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(300 mg, 1.1 mmol) in dichloromethane (10 mL) was addeddiethylaminosulfur trifluoride (1.78 g, 11.1 mmol) at 0° C. The reactionmixture was stirred at 25° C. for 2 h and subsequently quenched byaddition of ice-water (20 mL). The mixture was extracted withdichloromethane (3×20 mL). The combined organic layers were washed withwater (20 mL), brine (20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude ethyl7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxylateas a yellow oil (280 mg, 86%), used in the next step without furtherpurification. LCMS R_(T)=0.834 min, m/z=294.1 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.834 min, ESI+ found [M+H]=294.1.

Step 11:7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid

To a solution of ethyl7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(280 mg, 0.95 mmol) in tetrahydrofuran (10 mL) and water (2 mL) wasadded lithium hydroxide monohydrate (200 mg, 4.8 mmol). The reactionmixture was stirred at 25° C. for 3 h and subsequently concentratedunder reduced pressure. The residue was adjusted to pH=5 by additionalof hydrochloric acid (2 N). The resulting mixture was extracted withethyl acetate (3×20 mL). The combined organic layers were washed withwater (20 mL), brine (20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid as a yellow solid (240 mg, 95%), used in the next step withoutfurther purification.

Step 12:(3,3-difluoroazetidin-1-yl)-(7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

A mixture of7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (40 mg, 0.15 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (30 mg, 0.18mmol), 1-hydroxybenzotriazole (20 mg, 0.18 mmol) and3,3-difluoroazetidine hydrochloride (0.02 g, 0.18 mmol) inN,N-dimethylformamide (4 mL) was stirred at 25° C. for 16 h andsubsequently concentrated under reduced pressure. The residue waspurified by RP-HPLC (acetonitrile 30-60%/0.05% ammonium hydroxide inwater) to afford(3,3-difluoroazetidin-1-yl)-(7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone(10 mg, 30%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 7.45-7.42 (m,3H), 7.28-7.25 (m, 2H), 5.94-5.89 (m, 1H), 4.98-4.93 (m, 2H), 4.53 (t,J=12.0 Hz, 2H), 3.90-3.82 (m, 1H), 3.27-3.19 (m, 1H). LCMS R_(T)=0.713min, m/z=340.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time: 0.713 min, ESI+ found [M+H]=340.9.

Step 13:(S)-(7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3,3-difluoroazetidin-1-yl)methanoneand &(R)-(7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3,3-difluoroazetidin-1-yl)methanone

Racemic(3,3-difluoroazetidin-1-yl)-(7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4] triazol-2-yl)methanone (30 mg, 0.09 mmol) was separatedby chiral SFC to arbitrarily afford:

(S)-(7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3,3-difluoroazetidin-1-yl)methanone (peak 1, retention time=3.080 min) (6.3 mg, 21%)as white solids. ¹H NMR (400 MHz, CD₃OD) δ 7.46-7.37 (m, 3H), 7.30-7.20(m, 2H), 5.94-5.86 (m, 1H), 4.96-4.92 (m, 2H), 4.51 (t, J=12.0 Hz, 2H),3.91-3.82 (m, 1H), 3.27-3.23 (m, 1H). LCMS R_(T)=1.024 min, m/z=341.1[M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0mins) retention time: 1.025 min, ESI+ found [M+H]=341.1.

(R)-(7,7-difluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(3,3-difluoroazetidin-1-yl)methanone (peak 2, retention time=3.545 min) (5.8 mg, 19%)as white solid, ¹H NMR (400 MHz, CD₃OD) δ 7.44-7.39 (m, 3H), 7.25-7.23(m, 2H), 5.94-5.86 (m, 1H), 4.97-4.91 (m, 2H), 4.51 (t, J=12.0 Hz, 2H),3.88-3.78 (m, 1H), 3.26-3.21 (m, 1H). LCMS R_(T)=1.025 min, m/z=341.2[M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0mins) retention time: 1.025 min, ESI+ found [M+H]=341.2.

SFC conditions: Column: ChiralPak AD-3 150×4.6 mm I.D., 3 um; Mobilephase: A: CO₂ B:Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min; Flow rate: 2.5mL/min; Column temperature:40° C.

(3,3-difluoroazetidin-1-yl)-[(5R)-7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (6.0 mg, 39% yield)

Purification:

SFC condition: Column: Chiralpak IG 150×21.2 mm I.D., Mobile phase: A:CO2 B:Methanol (0.1% NH40H) Isocratic: 15%: 70 mL/min Columntemperature: 40° C.

Analytical:

Peak 2: Acquisition Method 15_Isocratic 10% MeOH, UV Wavelength: PDASingle 220.0 nm, Column: Chiralpak IG, Run Time: 2.5 Minutes,Co-Solvent: MeOH w/0.1% NH40H Injection Volume: 2.00 ul, ColumnTemp:40.0

Example 2, Method #2

(3,3-difluoroazetidin-1-yl)-[rac-(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Step 1: trans-ethyl7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution ofcis-ethyl-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(100 mg, 0.37 mmol) in dichloromethane (8 mL) was addeddiethylaminosulfur trifluoride (176.9 mg, 1.10 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 2 h and then quenched byaddition of water (20 mL). The mixture was extracted withdichloromethane (3×20 mL). The combined organic layers were washed withwater (20 mL), brine (20 mL), dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by preparative TLC (50%ethyl acetate in petroleum ether, Rf=0.5) to affordtrans-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(30 mg, 30%) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.37(m, 3H), 7.14-7.12 (m, 2H), 6.14 (d, J=5.2 Hz, 0.5H), 6.00 (d, J=5.2 Hz,0.5H), 5.74-5.71 (m, 1H), 4.51-4.45 (m, 2H), 3.42-3.35 (m, 1H),3.07-2.96 (m, 1H), 1.42 (t, J=7.2 Hz, 3H).

Step 2: trans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

To a solution oftrans-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(30 mg, 0.11 mol) in tetrahydrofuran (4 mL) and water (1 mL) was addedlithium hydroxide monohydrate (14 mg, 0.33 mmol). The reaction mixturewas stirred at 25° C. for 2 h and then concentrated under reducedpressure. The residue was adjusted to pH=5 by addition of hydrochloricacid (2 N). The mixture was extracted with ethyl acetate (3×20 mL). Thecombined organic layers were washed with water (20 mL), brine (20 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford crudetrans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid as white solid (13 mg, 48%), used in the next step without furtherpurification.

Step 3:(3,3-difluoroazetidin-1-yl)-[(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (trans mixture)

A mixture oftrans-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (13 mg, 0.05 mmol), 3,3-difluoroazetidine hydrochloride (14 mg,0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride(15 mg, 0.08 mmol) and 1-hydroxybenzotriazole (8 mg, 0.06 mmol) inN,N-dimethylformamide (2 mL) was stirred at 30° C. for 12 h. The mixturewas concentrated under reduced pressure and the residue was purified byRP-HPLC (35 to 65% acetonitrile in water+0.05% ammonia water) to afford(3,3-difluoroazetidin-1-yl)-[(5R,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone (trans mixture) (11.6 mg, 68%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 7.44-7.38 (m, 3H), 7.28-7.24 (m, 2H),6.26-6.10 (m, 1H), 5.88-5.84 (m, 1H), 4.95-4.92 (m, 2H), 4.51 (t, J=12.0Hz, 2H), 3.45-3.30 (m, 1H), 3.16-3.04 (m, 1H). LCMS R_(T)=0.961 min,m/z=323.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2mins) retention time 0.961 min, ESI+ found [M+H]=323.2.

Example 3, Method #3

(3,3-difluoroazetidin-1-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(cis mixture)

Step 1:trans-1-amino-3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one

To a solution oftrans-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one (7.0 g,24.0 mmol) in N,N-dimethylformamide (200 mL) was added sodium hydride(1.44 g, 36.0 mmol) at 0° C. and the mixture was stirred at 0° C. for 20min. Then o-(diphenylphosphoryl)hydroxylamine (8.40 g, 36.03 mmol) wasadded. The reaction mixture was stirred at 25° C. for 16 hours. Themixture was filtered and the filtrate was concentrated under reducedpressure to affordtrans-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one(7.0 g, 95.1%) as a yellow oil, use in the next step without furtherpurification. LCMS R_(T)=0.775 min, m/z=307.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.775 min, ESI+ found [M+H]=307.0.

Step 2: trans-ethyl2-(3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidin-1-yl)amino)-2-iminoacetate

To a solution oftrans-1-amino-3-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-pyrrolidin-2-one(7.0 g, 22.8 mmol) in ethanol (150 mL) was added ethyl2-ethoxy-2-imino-acetate (6.63 g, 45.7 mmol). The reaction mixture wasstirred at 60° C. for 16 h and subsequently concentrated under reducedpressure to afford crude trans-ethyl2-(3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidin-1-yl)amino)-2-iminoacetate(8.50 g, 92%) as a yellow oil, used in the next step without furtherpurification.

LCMS R_(T)=2.154 min, m/z=406.3 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3.0mins) retention time 2.143 min, ESI+ found [M+H]=406.3

Step 3: trans-ethyl7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl2-[[trans-3-[tert-butyl(dimethyl)silyl]oxy-2-oxo-5-phenyl-pyrrolidin-1-yl]amino]-2-imino-acetate(8.5 g, 21.0 mmol) in toluene (100 mL) was added p-toluenesulfonic acid(4.4 g, 25.2 mmol). The reaction mixture was stirred at 120° C. for 16and subsequently concentrated under reduced pressure to afford crudetrans-ethyl7-((tert-butyldimethylsilyl)oxy)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(7.5 g, 92.3%) as a yellow oil, used in the next step without furtherpurification. LCMS R_(T)=1.022 min, m/z=374.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2mins) retention time 1.022 min, ESI+ found [M+H]=374.2.

Step 4: trans-ethyl7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyltrans-7-[tert-butyl(dimethyl)silyl]oxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(7.0 g, 18.06 mmol) in tetrahydrofuran (120 mL) was addedtetrabutylammonium fluoride (1 N in THF, 18.06 mL, 18.06 mmol). Thereaction mixture was stirred at 40° C. for 3 h and subsequentlyconcentrated under reduced pressure to afford crude trans-ethyl7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(3.5 g, 57%) as a yellow oil, used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃): δ 7.39-7.35 (m, 3H), 7.14-7.12(m, 2H), 5.73-5.70 (m, 1H), 5.54-5.51 (m, 1H), 4.47-4.40 (m, 2H),3.24-3.21 (m, 1H), 3.05-3.00 (m, 1H), 1.41-1.36 (m, 3H).

Step 5: cis-ethyl7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of trans-ethyl7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(100 mg, 0.37 mmol) in dichloromethane (8 mL) was addeddiethylaminosulfur trifluoride (176.9 mg, 1.10 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 2 h and subsequently quenchedby addition of water (20 mL). The resulting mixture was extracted withdichloromethane (3×20 mL). The combined organic layers were washed withwater (20 mL), brine (20 mL), dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by preparative TLC (50%ethyl acetate in petroleum ether, Rf=0.5) to affordcis-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(54 mg, 54%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.31(m, 3H), 7.25-7.17 (m, 2H), 6.09 (dd, J=1.4 Hz, 7.2 Hz, 1H), 5.95 (dd,J=1.4 Hz, 7.2 Hz, 1H), 5.52-5.47 (m, 1H), 4.53-4.37 (m, 2H), 3.74-3.54(m, 1H), 3.05-2.82 (m, 1H), 1.48-1.33 (m, 3H).

Step 6:cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid

To a solution ofcis-ethyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(54 mg, 0.20 mol) in tetrahydrofuran (4 mL) and water (1 mL) was addedlithium hydroxide monohydrate (25 mg, 0.59 mmol). The reaction mixturewas stirred at 25° C. for 2 h and subsequently concentrated underreduced pressure. The residue was adjusted to pH=5 by addition ofhydrochloric acid (2 N. The resulting mixture was extracted with ethylacetate (3×10 mL). The combined organic layers were washed with water(10 mL), brine (10 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crudecis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (45 mg, 93%) as a white solid, used in the next step withoutfurther purification.

Step 7:(3,3-difluoroazetidin-1-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(cis mixture)

A mixture ofcis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (20 mg, 0.08 mmol), 3,3-difluoroazetidine hydrochloride (12 mg,0.08 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride(19 mg, 0.10 mmol) and 1-hydroxybenzotriazole (11 mg, 0.08 mmol) inN,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 h. The mixturewas concentrated under reduced pressure and the residue was purified byRP-HPLC (35 to 65% acetonitrile in water+0.05% ammonia water) to afford(3,3-difluoroazetidin-1-yl)-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(cis mixture) (13.5 mg, 51%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ7.44-7.38 (m, 3H), 7.28-7.24 (m, 2H), 6.17-6.02 (m, 1H), 5.65-5.62 (m,1H), 4.95-4.92 (m, 2H), 4.52 (t, J=12.0 Hz, 2H), 3.82-3.68 (m, 1H),2.86-2.76 (m, 1H). LCMS R_(T)=1.670 min, m/z=323.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2mins) retention time 1.670 min, ESI+ found [M+H]=323.1.

Example 4, Method #4

(3,3-difluoroazetidin-1-yl)-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Step 1: 1-amino-3-phenylpyrrolidin-2-one

To a solution of tert-butyl N-(2-oxo-3-phenyl-pyrrolidin-1-yl)carbamate(1.4 g, 5.1 mmol) in ethyl acetate (20 mL) was added HCl (4N in ethylacetate, 12.0 mL, 48.0 mmol). The mixture was stirred at 20° C. for 3 hand concentrated under reduced pressure. The residue was slowly quenchedby addition of saturated sodium bicarbonate (30 mL). The resultingsolution was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over sodium sulfate and concentrated to givecrude 1-amino-3-phenyl-pyrrolidin-2-one (590 mg, 66%) as a white solid,used as is in the next step.

Step 2: ethyl 2-imino-2-((2-oxo-3-phenylpyrrolidin-1-yl)amino)acetate

To a solution of 1-amino-3-phenyl-pyrrolidin-2-one (590 mg, 3.35 mmol)in ethanol (10 mL) was added ethyl 2-ethoxy-2-imino-acetate (1458 mg,10.04 mmol). The mixture was stirred at 40° C. for 12 h and concentratedunder reduced pressure to obtain crude ethyl(2Z)-2-amino-2-(2-oxo-3-phenyl-pyrrolidin-1-yl)imino-acetate (1370 mg,100%), used as is in the next step.

Step 3: Ethyl7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A solution of ethyl(2Z)-2-amino-2-(2-oxo-3-phenyl-pyrrolidin-1-yl)imino-acetate (1370 mg,4.98 mmol) in phosphorus oxychloride (5 mL) as stirred at 120° C. for 1h. After cooled, the mixture was slowly quenched by addition ofsaturated sodium bicarbonate (20 mL) and extracted with dichloromethane(3×20 mL). The combined organic layers were washed with brine (30 mL),dried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,0 to 50% ethyl acetate in petroleum ether) to afford ethyl7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (390mg, 31%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ7.40-7.14 (m,5H), 4.45 (q, J=8.0 Hz, 4H), 4.40-4.36 (m, 1H), 4.26-4.23 (m, 1H),3.29-3.22 (m, 1H), 2.78-2.70 (m, 1H), 1.40 (t, J=7.2 Hz, 3H). LCMSR_(T)=1.95 min, m/z=258.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.05% ammonium hydroxide over 3mins) retention time 1.95 min, ESI+ found [M+H]=258.1.

Step 4:7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid

A mixture of ethyl (7S)-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (340 mg, 1.32 mmol) and lithium hydroxide hydrate(555 mg, 13.22 mmol) in tetrahydrofuran (5 mL) and water (5 mL) wasstirred at 20° C. for 12 h. The organic solvent was evaporated underreduced pressure and the aqueous residue was adjusted to pH=2-3 byaddition of 20% HCl. The mixture was extracted with dichloromethane(5×30 mL). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure to afford the crude7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid(260 mg, 85%) as a yellow solid, used as is in the next step.

Step 5:(3,3-difluoroazetidin-1-yl)-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

A mixture of 3,3-difluoroazetidine hydrochloride (31 mg, 0.24 mmol),1H-benzo[d][1,2,3]triazol-1-ol (9 mg, 0.070 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (63 mg, 0.33mmol) and7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid(50 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C.for 3 h. The mixture was concentrated under reduced pressure and theresidue was purified by RP-HPLC (acetonitrile 20-50%/0.05% ammoniahydroxide in water) to afford(3,3-difluoroazetidin-1-yl)-(7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone(13 mg, 19%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.32 (m,2H), 7.31-7.24 (m, 3H), 4.99-4.92 (m, 2H), 4.57-4.47 (m, 3H), 4.45-4.37(m, 1H), 4.32-4.23 (m, 1H), 3.30-3.24 (m, 1H), 2.75-2.63 (m, 1H). LCMSR_(T)=0.782 min, m/z=304.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5mins) retention time 0.782 min, ESI+ found [M+H]=304.9.

Example 5, Method #5

(3,3-difluoroazetidin-1-yl)-(8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-yl)methanone

Step 1: 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole

To a solution of 3,5-dibromo-1H-1,2,4-triazole (10 g, 44.1 mmol) inacetonitrile (100 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran(8.0 mL, 52.9 mmol) and N,N-diisopropylethylamine (8.45 mL, 48.5 mmol).The mixture was stirred at 90° C. for 3 h and concentrated under reducedpressure. The residue was diluted with ethyl acetate (300 mL), washedsaturated sodium bicarbonate (2×50 mL), brine (2×50 mL), dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 100-200 mesh, 0 to 20%ethyl acetate in petroleum ether) to afford3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (13 g,83%) as a colorless oil, used as is in the next step.

Step 2:[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-phenyl-methanol

To a solution of3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (2.0 g,5.6 mmol) in tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M inhexanes, 2.6 mL, 6.5 mmol) at −78° C. The mixture was stirred at −78° C.for 1 h and then a solution of benzaldehyde (1.2 g, 11.3 mmol) in THF (2mL) was added. After addition, the mixture was stirred at −78° C. foranother 1 h and then quenched by addition of saturated ammonium chloride(10 mL). The resulting mixture was diluted with ethyl acetate (100 mL),washed with water (20 mL), brine (20 mL), dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate inpetroleum ether) to afford[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-phenyl-methanol(1.5 g, 69.7%) as a light yellow oil, used as is in the next step.

Step 3:2-bromo-8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine

A mixture of[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-phenyl-methanol(1.5 g, 3.92 mmol) and p-toluenesulfonic acid (863 mg, 5.02 mmol) intoluene (50 mL) was heated at reflux for 5 h. After cooled, the reactionwas diluted with ethyl acetate (100 mL), washed with sodium hydroxide(1N, 20 mL), brine (20 mL), dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0 to 40% ethyl acetate inpetroleum ether) to afford2-bromo-8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine (800mg, 73%) as a yellow oil. LCMS R_(T)=0.642 min, m/z=281.6 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.642 min, ESI+ found [M+H]=281.6

Step 4: methyl8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate

A mixture of 1,1′-bis(diphenylphosphino)ferrocene palladium dicholoride(13 mg, 0.02 mmol),2-bromo-8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine (300mg, 1.07 mmol) and triethylamine (1.45 mL, 10.7 mmol) in methanol (30mL) was heated at 70° C. for 12 h under CO (40 psi). The mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,0 to 50% ethyl acetate in petroleum ether) to afford methyl8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate (100 mg, 20%) as a brown oil.

LCMS R_(T)=0.682 min, m/z=259.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.682 min, ESI+ found [M+H]=259.9

Step 5:8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylicacid

A mixture of methyl8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate(50 mg, 0.11 mmol) and lithium hydroxide (8 mg, 0.32 mmol) intetrahydrofuran (4 mL) and water (1 mL) was stirred at 25° C. for 1 h.The mixture was adjusted to pH=3 by addition of 2N HCl and extractedwith ethyl acetate (2×10 mL). The combined organic layers wereconcentrated under reduced pressure to afford crude8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylicacid (25 mg, 94% crude yield) as a yellow solid, used as is in the nextstep.

Step 6:(3,3-difluoroazetidin-1-yl)-(8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-yl)methanone

A mixture of 3,3-difluoroazetidine hydrochloride (14.9 mg, 0.12 mmol),1H-benzo[d][1,2,3]triazol-1-ol (4.3 mg, 0.030 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (30 mg, 0.16mmol) and8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylicacid (26 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) was stirred at30° C. for 15 h. The mixture was concentrated under reduced pressure andthe residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammoniahydroxide in water) to afford(3,3-difluoroazetidin-1-yl)-(8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-yl)methanone(2.65 mg, 8%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 7.43-7.36 (m,5H), 5.97 (s, 1H), 4.54-4.43 (m, 4H), 4.43-4.14 (m, 4H).

LCMS R_(T)=1.559 min, m/z=321.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium hydroxide over 3minutes) retention time 1.559 min, ESI+ found [M+H]=321.1.

Example 6, Method #6

(3,3-difluoroazetidin-1-yl)-[8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-yl]methanone

Step 1:(3-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-1,2,4-triazol-5-yl)(2-fluorophenyl)methanol

To a solution of3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (2.0 g,5.6 mmol) in tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M inhexanes, 2.6 mL, 6.5 mmol) at −78° C. The mixture was stirred at −78° C.for 1 h and then a solution of 2-fluorobenzaldehyde (1.4 g, 11.27 mmol)in THF (2 mL) was added. After addition, the mixture was stirred at −78°C. for another 1 h and then quenched by addition of saturated ammoniumchloride (10 mL). The resulting mixture was diluted with ethyl acetate(100 mL), washed with water (20 mL), brine (20 mL), dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 100-200 mesh, 0 to 20%ethyl acetate in petroleum ether) to afford[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-(2-fluorophenyl)methanol(1.0 g, 44%) as a light yellow oil. LCMS R_(T)=0.64 min, m/z=401.7[M+H]⁺. LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acidover 1.5 mins) retention time 0.64 min, ESI+ found [M+H]=401.7.

Step 2:2-bromo-8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine

A mixture of[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-(2-fluorophenyl)methanol(1000 mg, 2.5 mmol) and p-toluenesulfonic acid (546 mg, 3.17 mmol) intoluene (20 mL) was heated at reflux for 3 h. The mixture wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetatein petroleum ether) to give2-bromo-8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine(300 mg, 40.3%) as yellow solid, used as is in the next step.

Step 3: Methyl8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate

A mixture of2-bromo-8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine(290 mg, 0.97 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladiumdichloride (13 mg, 0.02 mmol), and triethylamine (1.31 mL, 9.73 mmol) inmethanol (10 mL) was heated at 80° C. for 16 h under CO (25 psi) andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (silica gel, 100-200 mesh,100% dichloromethane) to give methyl8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate(200 mg, 74%) as colorless oil. LCMS R_(T)=0.59 min, m/z=277.8 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.59 min, ESI+ found [M+H]=277.8.

Step 4:8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylicacid

A mixture of methyl8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylate (200 mg, 0.72 mmol) and potassium hydroxide (80mg, 1.44 mml) in ethanol (20 mL) and water (5 mL) was stirred at 25° C.for 1 h. The ethanol was evaporated under reduced pressure and theaqueous residue was adjusted to pH=3 by addition of 2N HCl. The solutionwas extracted with ethyl acetate (2×10 mL). The combined organic layerswere concentrated to give crude8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylicacid (180 mg, 94%) as a yellow solid, used as is in the next step.

Step 5:(3,3-difluoroazetidin-1-yl)-[8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4] oxazin-2-yl] methanone

A mixture of 3,3-difluoroazetidine hydrochloride (14 mg, 0.11 mmol),1-hydroxybenzotriazole (12 mg, 0.09 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (17 mg, 0.09mmol) and8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazine-2-carboxylicacid (20 mg, 0.08 mmol) in N,N-dimethylformamide (3 mL) was stirred at25° C. for 12 h. The mixture was concentrated under reduced pressure andthe residue was purified by RP-HPLC (acetonitrile 20% to 50%/0.05%ammonia hydroxide in water) to afford(3,3-difluoroazetidin-1-yl)-[8-(2-fluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-yl]methanone(6.0 mg, 23%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (d,J=6.4 Hz, 1H), 7.38 (t, J=6.8 Hz, 1H), 7.30-7.18 (m, 2H), 6.18 (s, 1H),4.81-4.73 (m, 2H), 4.57-4.31 (m, 4H), 4.29-4.08 (m, 2H). LC-MSR_(T)=1.713 min, m/z=339.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 3.0mins) retention time 1.713 min, ESI+ found [M+H]=339.2.

Example 7, Method #7

(3,3-difluoroazetidin-1-yl)-[(1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridin-6-yl]methanone

4,6-dichloro-1-ethyl-1-methylfuro[3,4-c]pyridin-3(1H)-one

n-BuLi (2.5 M in hexane, 16 mL, 40 mmol) was added dropwise to asolution of diisopropylamine (4.7 g, 46.5 mmol) at −78° C. The mixturewas stirred at −78° C. for 40 min and a solution of2,6-dichloronicotinic acid (3 g, 15.6 mmol) in tertahydrofuran (30 mL)was added dropwise to the reaction mixture at −78° C. and the resultantmixture was stirred at −78° C. for 3 h. Butanone (10 g, 139 mmol) wasadded dropwise to the reaction mixture at −78° C. and the reactionmixture was warmed slowly to RT and stirred for 16 h. The reactionmixture was cooled to 0° C., quenched with sat. ammonium chloride to pH7 and acidified with 3 N HCl to pH 4. The mixture was extracted withethyl acetate (30 mL×4). The combined organic layers were combined,dried over sodium sulphate and concentrated to dryness in vacuo. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,8:1 to 6:1 to 4:1 ethyl acetate: petroleum ether) to afford4,6-dichloro-1-ethyl-1-methylfuro[3,4-c]pyridin-3(1H)-one as a brownsolid (1.3 g, Yield 34%). LCMS: m/z=246.0/248.1 [M+1], Column: MERCKRP18 (50-3). Mobile phase: H₂O(0.01% TFA) (A)/ACN(0.01% TFA)(B) Elutionprogram: Gradient from 10 to 95% of B inl.8 min at 2.0 ml/min.Temperature: 45° C. 3 min gradient.

4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol

To a stirred suspension of4,6-dichloro-1-ethyl-1-methylfuro[3,4-c]pyridin-3(1H)-one (1.3 g, 5.28mmol) in toluene (30 mL) was added diisobutyl aluminium hydride (1 M intoluene, 12 mL, 12 mmol) at −78° C. The reaction mixture was stirred at−78° C. for 1.5 h and quenched with saturated ammonium chloride (50 ml)dropwise at −78° C. The mixture was warmed slowly to R_(T) and stirredfor 30 min. The reaction mixture was filtered and the filtrate wasextracted with ethyl acetate (30 mL×3). The combined organic layers werecombined, dried over sodium sulfate and concentrated to dryness invacuo. The residue was purified by column chromatography (silica gel,100-200 mesh, 4:1 to 2:1 ethyl acetate: petroleum ether) to afford4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (1 g,Yield 76%) as a colorless oil: LCMS: m/z=248.0/250.1 [M+1], Column:MERCK RP18 (50-3). Mobile phase: H₂O(0.01% TFA) (A)/ACN(0.01% TFA)(B)Elution program: Gradient from to 95% of B in 1.8 min at 2.0 ml/min.Temperature: 45° C. 3 min gradient.

4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine

To a stirred solution of4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridin-3-ol (1 g,4.06 mmol) in dichloromethane (10 ml) was added dropwise trifluoroaceticacid (1.5 mL, 20.1 mmol) at 0° C. and the mixture was stirred at 0° C.for 30 min. Triethylsilane (2 mL, 12.55 mmol) was added dropwise to thereaction mixture at 0° C. and the reaction mixture was warmed slowly toRT and stirred at RT for 2 h. The reaction mixture was concentrated todryness in vacuo. The residue was dissolved in ethyl acetate (50 mL) andadjusted to pH=7 by addition of saturated sodium bicarbonate. The ethylacetate layer was separated, dried over sodium sulphate and concentratedto dryness in vacuo. The residue was purified by column chromatography(silica gel, 100-200 mesh, 8:1 ethyl acetate: petroleum ether) to afford4,6-dichloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine (0.83 g,Yield 88%) was got as a white solid. LCMS: m z=232.1/234.1 [M+1],Column: MERCK RP18 (50-3). Mobile phase: H₂O(0.01% TFA) (A)/ACN(0.01%TFA)(B) Elution program: Gradient from 10 to 95% of B in 1.8 min at 2.0ml/min. Temperature: 45° C. 3 min gradient.

Methyl4-chloro-1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylateand methyl 6-chloro-1-ethyl-1-methyl-1,3-dihydrofuro [3,4-c]pyridine-4-carboxylate

To a solution of 4,6-dichloro-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine(0.50 g, 2.15 mmol) in methanol (10 mL) was added[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.16 g,0.22 mmol) and triethylamine (2.18 g, 21.54 mmol). The reaction mixturewas stirred at 80° C. for 15 h under the carbon monoxide (25 psi). Aftercooling to R_(T) the reaction mixture was concentrated to dryness invacuo. The residue was purified by column chromatography (silica gel,100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to affordmethyl 4-chloro-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylateand methyl6-chloro-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-4-carboxylate (140 mg(3:1 mixture), 0.55 mmol, 25.5% yield mixture) as a light yellow oilused as is in the next step without further purification.

Methyl 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate andmethyl 1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-4-carboxylate

To a solution of methyl4-chloro-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylate andmethyl 6-chloro-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-4-carboxylate(140 mg, 0.55 mmol) in methanol (10 mL) was added 10% palladium (437 mg,0.41 mmol) on carbon. The reaction mixture was hydrogenated (15 psi) at20° C. for 1 h and then filtered through Celite. The filtrate wasconcentrated to dryness in vacuo to afford methyl1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-4-carboxylate and methyl1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylate (100 mg, 82.6%yield) as a yellow oil: LCMS (5 to 95% acetonitrile in water+0.03%trifluoacetic acid over 1.5 mins) retention time 0.65 min, ESI+ found[M+H]=222.

1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid and1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-4-carboxylic acid

To a solution of methyl1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate and methyl1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-4-carboxylate (100 mg,0.46 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added lithiumhydroxide monohydrate (202 mg, 4.81 mmol). The reaction mixture wasstirred at 15° C. for 15 h and concentrated to dryness in vacuo. Theresidue was diluted with water (5 mL) and adjusted to pH=3 by additionof 1 M hydrochloric acid. The mixture was extracted with dichloromethane(3×15 mL). The combined organic layers were dried over sodium sulfateand concentrated to dryness in vacuo to afford1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-6-carboxylic acid and1-ethyl-1-methyl-1,3-dihydrofuro[3,4-c]pyridine-4-carboxylic acid (50mg, 50.5% yield) as a yellow oil used in the next step without furtherpurification.

(3,3-difluoroazetidin-1-yl)-[(1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridin-6-yl]methanone

A mixture of 3,3-difluoroazetidine hydrochloride (34 mg, 0.27 mmol),1-hydroxybenzotriazole (39 mg, 0.29 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (55 mg, 0.29mmol) and (1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridine-6-carboxylic acid(50 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25° C.for 12 h. The mixture was concentrated under reduced pressure and theresidue was purified by RP-HPLC (acetonitrile 38% to 48%/0.05% ammoniahydroxide in water) to afford(3,3-difluoroazetidin-1-yl)-[(1R)-1-ethyl-1-methyl-3H-furo[3,4-c]pyridin-6-yl]methanone(29.6 mg, 43%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H),7.92 (s, 1H), 5.20-5.12 (m, 2H), 5.06 (t, J=12.0 Hz, 2H), 4.54 (t,J=12.0 Hz, 2H), 1.87 (q, J=7.6 Hz, 2H), 1.48 (s, 3H), 0.79 (t, J=7.6 Hz,3H). LC-MS R_(T)=1.699 min, m/z=283.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% ammonium bicarbonate over3.0 mins) retention time 1.699 min, ESI+ found [M+H]=283.1.

Example 8, Method #8

(3,3-difluoroazetidin-1-yl)-[5-(1,1-difluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Step 1: 1,5-diacetylpyrrolidin-2-one

A mixture of D-glutamic acid (5.0 g, 33.98 mmol) and4-dimethylaminopyridine (249.11 mg, 2.04 mmol) in acetic anhydride (10.9mL, 115.54 mmol) and triethylamine (15.02 mL, 107.73 mmol) was stirredat 60° C. for 15 h and then concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,0 to 40% ethyl acetate in petroleum ether) to afford1,5-diacetylpyrrolidin-2-one (3.0 g, 52%) as yellow oil. ¹H NMR (400MHz, CDCl₃) δ 4.88-4.85 (m, 1H), 2.66-2.56 (m, 2H), 2.53 (s, 3H),2.29-2.24 (m, 4H), 1.93-1.92 (m, 1H).

Step 2: 1-acetyl-5-(1,1-difluoroethyl)pyrrolidin-2-one

To a solution of 1,5-diacetylpyrrolidin-2-one (450 mg, 2.66 mmol) indichloromethane (15 mL) was added diethylaminosulfur trifluoride (4.3 g,26.6 mmol) at 25° C. The reaction mixture was stirred at 50° C. for 16 hand then concentrated under reduced pressure. The residue was purifiedby column chromatography (silica gel, 100-200 mesh, 0 to 20% ethylacetate in petroleum ether) to afford1-acetyl-5-(1,1-difluoroethyl)pyrrolidin-2-one (170 mg, 33%) as a yellowoil, used in the next step as is.

Step 3: 5-(1,1-difluoroethyl)pyrrolidin-2-one

To a solution of 1-acetyl-5-(1,1-difluoroethyl)pyrrolidin-2-one (60 mg,0.30 mmol) in methanol (5 mL) was added sodium hydride (60%, 6 mg, 0.15mmol). The reaction mixture was stirred at 25° C. for 12 h andsubsequently concentrated under reduced pressure to afford crude of5-(1,1-difluoroethyl)pyrrolidin-2-one (60 mg, 68%, 50% purity) as yellowoil, used in the next step without further purification.

Step 4: 1-amino-5-(1,1-difluoroethyl)pyrrolidin-2-one

To a solution of 5-(1,1-difluoroethyl)pyrrolidin-2-one (60 mg, 0.4 mmol)in N,N-dimethylformamide (5 mL) was added sodium hydride (60%, 24 mg,0.6 mmol) at 0° C. After addition, the mixture was stirred at 0° C. for30 min and O-(diphenylphosphoryl)hydroxylamine (141 mg, 0.6 mmol) wasadded. The reaction mixture was stirred at 25° C. for 16 h and filtered.The filtrate was concentrated under reduced pressure and the residue waspurified by preparative TLC (100% ethyl acetate in petroleum ether,Rf=0.4) to afford 1-amino-5-(1,1-difluoroethyl)pyrrolidin-2-one (30 mg,45%) as a yellow oil.

LCMS R_(T)=0.716 min, m/z=165.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 3.0mins) retention time 0.716 min, ESI+ found [M+H]=165.1.

Step 5: ethyl2-[[2-(1,1-difluoroethyl)-5-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate

To a solution of 1-amino-5-(1,1-difluoroethyl)pyrrolidin-2-one (30 mg,0.18 mmol) in ethanol (3 mL) was added ethyl 2-ethoxy-2-imino-acetate(80 mg, 0.55 mmol). The reaction mixture was stirred at 60° C. for 16 hand concentrated under reduced pressure to afford the crude ethyl2-[[2-(1,1-difluoroethyl)-5-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate(40 mg, 83%) as a yellow oil, used in the next step without furtherpurification.

Step 6: ethyl5-(1,1-difluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of ethyl2-[[2-(1,1-difluoroethyl)-5-oxo-pyrrolidin-1-yl]amino]-2-imino-acetate(90 mg, 0.34 mmol) in phosphorus oxychloride (2.5 mL) was stirred at120° C. for 1 h and subsequently quenched by addition of water (20 mL).The resulting mixture was extracted with dichloromethane (3×20 mL). Thecombined organic layers were washed with saturated aqueous sodiumbicarbonate (20 mL), brine (20 mL), dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bycolumn chromatography (silica gel, 100-200 mesh, 0 to 70% ethyl acetatein petroleum ether) to afford ethyl5-(1,1-difluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(30 mg, 36%) as a light yellow oil. LCMS R_(T)=0.573 min, m/z=246.2[M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.573 min, ESI+ found [M+H]=246.2.

Step 7:5-(1,1-difluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid

A mixture of ethyl5-(1,1-difluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(30 mg, 0.12 mmol) and lithium hydroxide hydrate (41 mg, 0.98 mmol) intetrahydrofuran/methanol/water (5 mL, 2:2:1) was stirred at 25° C. for12 h and concentrated under reduced pressure. The residue was adjustedto pH=4-5 by addition of hydrochloric acid (1 M). The resulting mixturewas concentrated under reduced pressure to give crude5-(1,1-difluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (22 mg, 83%) as a yellow solid, used in the next step withoutfurther purification. LCMS R_(T)=0.819 min, m/z=218.1 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2.0mins) retention time 0.819 min, ESI+ found [M+H]=218.1.

Step 8:(3,3-difluoroazetidin-1-yl)-[5-(1,1-difluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

A mixture of5-(1,1-difluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (7 mg, 0.03 mmol), 1-hydroxybenzotriazole (7 mg, 0.05 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (9 mg, 0.05mmol) and 3,3-difluoroazetidine hydrochloride (4 mg, 0.03 mmol) inN,N-dimethylformamide (1 mL) was stirred at 25° C. for 4 h. The mixturewas concentrated under reduced pressure and the residue was purified byRP-HPLC (acetonitrile 25-55%/0.05% ammonium hydroxide in water) toafford(3,3-difluoroazetidin-1-yl)-[5-(1,1-difluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(4 mg, 42%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 4.98-4.95 (m,2H), 4.90-4.83 (m, 1H), 4.52 (t, J=12.0 Hz, 2H), 3.03-2.94 (m, 3H),2.88-2.85 (m, 1H), 1.82 (t, J=19.2 Hz, 3H). LC-MS R_(T)=0.738 min,m/z=292.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.738 min, ESI+ found [M+H]=292.9.

Example 9, Method #9

(3,3-difluoroazetidin-1-yl)-[(4R)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b] pyrazol-2-yl]methanone

Step 1: (2-bromoethoxy)(tert-butyl)diphenylsilane

To a solution of 2-bromoethanol (2.0 g, 16.0 mmol) and imidazole (3.27g, 48.0 mmol) in dichloromethane (20 mL) was addedtert-butyldiphenylchlorosilane (4.4 g, 16.01 mmol) at 0° C. Afteraddition, the reaction mixture was stirred at 25° C. for 16 h andsubsequently concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 100-200 mesh, petroleumether) to afford 2-bromoethoxy-tert-butyl-diphenyl-silane (3.1 g, 53%)as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (m, 4H), 7.47-7.37 (m,6H), 3.93 (t, J=6.4 Hz, 2H), 3.43 (t, J=6.5 Hz, 2H), 1.08 (s, 9H).

Step 2: 5-((tert-butyldiphenylsilyl)oxy)-3-phenylpentan-2-one

To a solution of phenylacetone (10.0 g, 74.5 mmol) inN,N-dimethylformamide (20 mL) was added sodium hydride (60%, 4.5 g,111.8 mmol) at 0° C. After addition, the mixture was stirred at 25° C.for 15 min and 2-bromoethoxy-tert-butyl-diphenyl-silane (32.5 g, 89.4mmol) was added. The resulting mixture was stirred at 25° C. for 18 hand subsequently quenched by addition of water (100 mL). The mixture wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with water (20 mL), brine (20 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 100-200 mesh, 0 to 20%ethyl acetate in petroleum ether) to afford5-[tert-butyl(diphenyl)silyl]oxy-3-phenyl-pentan-2-one as yellow oil(6.0 g, 19%). ¹H NMR (400 MHz, CDCl₃) δ 7.65-7.55 (m, 4H), 7.44-7.26 (m,9H), 7.22-7.15 (m, 2H), 3.99 (t, J=12 Hz, 1H), 3.65-3.58 (m, 1H),3.65-3.75 (m, 1H), 2.40-2.28 (m, 1H), 2.05 (s, 3H), 1.90-1.80 (m, 1H),1.05 (s, 9H).

Step 3: ethyl7-((tert-butyldiphenylsilyl)oxy)-2,4-dioxo-5-phenylheptanoate

To a solution of 5-[tert-butyl(diphenyl)silyl]oxy-3-phenyl-pentan-2-one(5.75 g, 13.8 mmol) in tetrahydrofuran (60 mL) was added potassiumtert-butoxide (1.0 M in tetrahydrofuran, 20.7 mL, 20.7 mmol) at 0° C.After addition, the mixture was stirred at 25° C. for 30 min and diethyloxalate (3.0 g, 20.7 mmol) was added. The resulting mixture was stirredat 25° C. for 2 h and concentrated under reduced pressure. The residuewas purified by column chromatography (silica gel, 100-200 mesh, 0 to50% ethyl acetate in petroleum ether) to afford ethyl7-[tert-butyl(diphenyl)silyl]oxy-2,4-dioxo-5-phenyl-heptanoate as abrown oil (6.0 g, 84%), used as is in the next step.

Step 4: ethyl3-(3-((tert-butyldiphenylsilyl)oxy)-1-phenylpropyl)-1H-pyrazole-5-carboxylate

A mixture of hydrazine monohydrate (684 mg, 11.6 mmol) and ethyl7-[tert-butyl(diphenyl)silyl]oxy-2,4-dioxo-5-phenyl-heptanoate (6.0 g,11.6 mmol) in ethanol (120 mL) was stirred at 25° C. for 5 h andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate inpetroleum ether) to afford ethyl3-[3-[tert-butyl(diphenyl)silyl]oxy-1-phenyl-propyl]-1H-pyrazole-5-carboxylate(1.8 g, 30%) as a light yellow oil. LCMS R_(T)=1.036 min, m/z=513.1[M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 1.036 min, ESI+ found [M+H]=513.1.

Step 5: ethyl 3-(3-hydroxy-1-phenylpropyl)-1H-pyrazole-5-carboxylate

To a solution of ethyl3-[3-[tert-butyl(diphenyl)silyl]oxy-1-phenyl-propyl]-1H-pyrazole-5-carboxylate(1.80 g, 3.5 mmol) in tetrahydrofuran (40 mL) was addedtetrabutylammonium fluoride (1.0 N in tetrahydrofuran, 3.9 mL, 3.9mmol). The mixture was stirred at 25° C. for 5 h and then concentratedunder reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0 to 50% ethyl acetate inpetroleum ether) to afford ethyl3-(3-hydroxy-1-phenyl-propyl)-1H-pyrazole-5-carboxylate as a lightyellow oil (800 mg, 83%), used as is in the next step.

Step 6: ethyl 3-(3-bromo-1-phenylpropyl)-1H-pyrazole-5-carboxylate

A mixture of phosphorusoxybromide (815 mg, 2.84 mmol) and ethyl5-(3-hydroxy-1-phenyl-propyl)-1H-pyrazole-3-carboxylate (650 mg, 2.37mmol) in acetonitrile (20 mL) was heated at 50° C. for 15 h andsubsequently concentrated under reduced pressure to afford crude ethyl5-(3-bromo-1-phenyl-propyl)-1H-pyrazole-3-carboxylate as brown solid(790 mg, 98%). This crude was used in the next step without furtherpurification.

Step 7: ethyl4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate

A mixture of ethyl 5-(3-bromo-1-phenyl-propyl)-1H-pyrazole-3-carboxylate(790 mg, 2.34 mmol) and potassium carbonate (2.59 g, 18.74 mmol) in N,A-dimc ihy 1 formamide (20 mL) was stirred at 25° C. for 5 h andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by preparative TLC (50% ethyl acetate in petroleumether, Rf=0.5) to afford ethyl4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (400 mg,67%) as a brown oil. LCMS R_(T)=0.850 min, m/z=257.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.850 min, ESI+ found [M+H]=257.0.

Step 8: 4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid

A mixture of ethyl4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (400 mg,1.56 mmol) and lithium hydroxide monohydrate (196 mg, 4.68 mmol) intetrahydrofuran (8 mL)/water (2 mL) was stirred at 25° C. for 2 h andconcentrated under reduced pressure. The residue was adjusted to pH=5 byaddition of hydrochloric acid (2 N). The resulting mixture was extractedwith ethyl acetate (3×10 mL). The combined organic layers were washedwith water (20 mL), brine (20 mL), dried over anhydrous sodium sulfateand concentrated under reduced pressure to afford crude4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid as abrown solid (340 mg, 95%), used in the next step without furtherpurification.

Step 9:(3,3-difluoroazetidin-1-yl)-[(4R)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanone

A mixture of 4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylicacid (100 mg, 0.44 mmol), 1-hydroxybenzotriazole (65 mg, 0.48 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (126 mg, 0.66mmol) and 3,3-difluoroazetidine hydrochloride (68 mg, 0.53 mmol) inN,N-dimethylformamide (4 mL) was stirred at 25° C. for 15 h. The mixturewas concentrated under reduced pressure and the residue was purified byRP-HPLC (acetonitrile 40-70%/0.05% ammonium hydroxide in water) toafford(3,3-difluoroazetidin-1-yl)-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanoneas a white solid (45 mg, 34%). LCMS R_(T)=1.824 min, m/z=304.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0mins) retention time: 1.824 min, ESI+ found [M+H]=304.1

The racemic(3,3-difluoroazetidin-1-yl)-(4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanone(45 mg, 0.15 mmol) was further separated by chiral SFC to affordarbitrarily assigned:(3,3-difluoroazetidin-1-yl)-[(4R)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanone (peak 2, retention time=2.757 min) as a white solid (19 mg,42%). ¹H NMR (400 MHz, CD₃OD) δ 7.35-7.30 (m, 2H), 7.30-7.21 (m, 3H),6.44 (s, 1H), 4.96-4.85 (m, 2H), 4.51-4.47 (m, 3H), 4.40-4.28 (m 1H),4.28-4.20 (m, 1H), 3.14-3.05 (m, 1H), 2.57-2.50 (m, 1H). LCMSR_(T)=1.040 min, m/z=304.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2.0mins) retention time: 1.040 min, ESI+ found [M+H]=304.2

SFC condition: Column: OJ(250 mm*30 mm, 5 um); Mobile phase: A: CO₂B:0.1% NH3H2O ETOH; Gradient: from 20% to 20% of B; Flow rate: 60mL/min. Column temperature: 40° C.

Example 10, Method #10

(3,3-difluoroazetidin-1-yl)-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Step 1: (R)-ethyl5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylateand (S)-ethyl5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

Racemic ethyl5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(7.1 g, 25.79 mmol) was separated by chiral SFC to afford arbitrarilyassigned:

(R)-ethyl5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(Peak 1, Retention time=3.325 min) (3.0 g, 42%) as a yellow oil.

(S)-ethyl5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(Peak 2, Retention time=3.560 min) (2.8 g, 39%) as a yellow oil.

SFC condition: Column: ChiralPak AD-3 150×4.6 mm I.D., 3 um Mobilephase: A: CO2 B: Ethanol (0.05% DEA) Gradient: from 5% to 40% of B in5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min Flow rate: 2.5mL/min Column temperature: 40° C.

Step 2:(S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid

To a solution of ethyl(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(2.0 g, 7.27 mmol) in tetrahydrofuran (50 mL)/water (10 mL) was addedlithium hydroxide hydrate (870 mg, 36.33 mmol) portion-wise. Thereaction mixture was stirred at 25° C. for 12 h and then concentratedunder reduce pressure. The aqueous residue was diluted with ice water(20 mL) and adjusted to pH=3 by addition of hydrochloric acid (1 N). Thesolid product was collected by filtration and dried in vacuo to affordcrude(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (1.6 g, 89%) as a white solid used as is in the next step. ¹H NMR(400 MHz, DMSO-d₆) δ 13.19 (br s, 1H), 7.48-7.40 (m, 1H), 7.31-7.20 (m,3H), 5.80-5.76 (m, 1H), 3.25-3.17 (m, 1H), 3.11-2.97 (m, 2H), 2.64-2.58(m, 1H). LCMS R_(T)=0.586 min, m/z=248.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5mins) retention time 0.586 min, ESI+ found [M+H]=248.0.

Step 3:(3,3-difluoroazetidin-1-yl)-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

A mixture of(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (20 mg, 0.08 mmol), 3,3-difluoroazetidine hydrochloride (15 mg,0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (19 mg, 0.10mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 15 h.The mixture was concentrated under reduced pressure and the residue waspurified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide inwater) to afford(3,3-difluoroazetidin-1-yl)-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(7.2 mg, 27%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.43-7.36 (m,1H), 7.23-7.10 (m, 3H), 5.80-5.77 (m, 1H), 4.96-4.86 (m, 2H), 4.48 (t,J=12.0 Hz, 2H), 3.38-3.31 (m, 1H), 3.19-3.02 (m, 2H), 2.70-2.67 (m, 1H).LCMS R_(T)=1.738 min, m/z=323.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 3.0mins) retention time 1.738 min, ESI+ found [M+H]=323.2.

Example 11, Method #11

(3,3-difluoroazetidin-1-yl)-[(5R)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Step 1:(R)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid

To a solution of ethyl(5R)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(1.0 g, 3.63 mmol) in tetrahydrofuran (30 mL)/water (15 mL) was addedlithium hydroxide hydrate (870 mg, 36.33 mmol) portionwise. The reactionmixture was stirred at 25° C. for 12 h and then concentrated underreduce pressure. The aqueous residue was diluted with ice water (20 mL)and adjusted to pH=3 by addition of hydrochloric acid (1 N). The solidproduct was collected by filtration and dried in vacuo to afford(5R)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (700 mg, 78%) as a white solid, used in the next step withoutfurther purification. LCMS R_(T)=0.986 min, m/z=248.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 2.0mins) retention time 0.986 min, ESI+ found [M+H]=248.2.

Step 2:(3,3-difluoroazetidin-1-yl)-[(5R)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

A mixture of(5R)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (20 mg, 0.08 mmol), 3,3-difluoroazetidine hydrochloride (15 mg,0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (19 mg, 0.10mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 15 h.The mixture was concentrated under reduced pressure and the residue waspurified by RP-HPLC (acetonitrile 22-52%/0.05% ammonium hydroxide inwater) to afford((3,3-difluoroazetidin-1-yl)-[(5R)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(7.4 mg, 28%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.44-7.35 (m,1H), 7.22-7.10 (m, 3H), 5.80-5.77 (m, 1H), 4.94-4.87 (m, 1H), 4.85-4.79(m, 1H), 4.48 (t, J=12.0 Hz, 2H), 3.36-3.31 (m, 1H), 3.20-3.01 (m, 2H),2.75-2.65 (m, 1H). LCMS R_(T)=1.737 min, m/z=323.2 [M+H]⁺.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoroacetic acid over 3.0mins) retention time 1.737 min, ESI+ found [M+H]=323.2.

Example 12, Method #12

Azetidin-1-yl-[(5R)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone

Amide coupling was prepared in a similar fashion to Method #11(G03093424, GNT E425 1029).

The crude was purified by RP-HPLC (acetonitrile 20-50%/0.05% ammoniumhydroxide in water) to affordazetidin-1-yl-[(5R)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(7.8 mg, 33%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.40-7.37 (m,1H), 7.19-7.11 (m, 3H), 5.79-5.75 (m, 1H), 4.58-4.53 (m, 2H), 4.19-4.15(m, 2H), 3.28-3.26 (m, 1H), 3.13-3.06 (m, 2H), 2.71-2.68 (m, 1H),2.39-2.31 (m, 2H). LCMS R_(T)=0.680 min, m/z=287.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5mins) retention time 0.680 min, ESI+ found [M+H]=287.0.

Example 13, Method #13

(3,3-difluoroazetidin-1-yl)-(4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methanone

Step 1: 3-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole

To a solution of 3-bromo-1H-pyrazole (5.0 g, 34.0 mmol) in acetonitrile(100 mL) was added cesium carbonate (16.6 g, 51.0 mmol) and2-(2-bromoethoxy)tetrahydro-2h-pyran (7.5 g, 35.7 mmol). The mixture wasstirred at 30° C. for 2 h and quenched by the addition of water (80 mL).The resulting mixture was extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with water (20 mL), brine (20 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel,100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford3-bromo-1-(2-tetrahydropyran-2-yloxyethyl)pyrazole (5.5 g, 59%) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J=2.4 Hz, 1H), 6.24 (d,J=1.2 Hz, 1H), 4.55-4.29 (m, 1H), 4.30-4.22 (m, 2H), 4.06-4.02 (m, 1H),3.75-3.68 (m, 1H), 3.65-3.60 (m, 1H), 3.46-3.45 (m, 1H), 1.76-1.49 (m,6H).

Step 2:(3-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-5-yl)(phenyl)methanol

To a solution of lithium diisopropylamide (10.9 mL, 21.8 mmol) intetrahydrofuran (100 mL) was added3-bromo-1-(2-tetrahydropyran-2-yloxyethyl)pyrazole (4.0 g, 14.5 mmol) intetrahydrofuran (2 mL) at −78° C. The resulting mixture was stirred at−78° C. for 30 min and benzaldehyde (1.8 g, 17.5 mmol) intetrahydrofuran (2 mL) was added. The reaction mixture was allowed towarm to room temperature over 18 h and quenched by the addition ofsaturated aqueous ammonium chloride (20 mL). The mixture was extractedwith ethyl acetate (3×100 mL). The combined organic layers were washedwith water (50 mL), brine (50 mL), dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bycolumn chromatography (silica gel, 100-200 mesh, 10 to 80% ethyl acetatein petroleum ether) to give[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)pyrazol-3-yl]-phenyl-methanol(3.5 g, 63%) as a colorless oil, used as is in the next step.

Step 3: 2-bromo-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine

To a solution of[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)pyrazol-3-yl]-phenyl-methanol(3.5 g, 9.18 mmol) was added p-toluenesulfonic acid (870 mg, 5.05 mmol).The reaction mixture was heated at reflux for 5 min and concentratedunder reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate inpetroleum ether) to afford2-bromo-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (1.1 g, 43%)as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.34 (m, 5H), 5.83(d, J=1.0 Hz, 1H), 5.71 (s, 1H), 4.36-4.28 (m, 2H), 4.24-4.17 (m, 1H),4.15-4.08 (m, 1H).

Step 4: butyl4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate

A mixture of 2-bromo-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine(110 mg, 0.39 mmol), palladium(II)acetate (9 mg, 0.04 mmol),1,3-bis(diphenylphosphino)propane (16 mg, 0.04 mmol) and triethylamine(0.55 mL, 3.94 mmol) in 1-butanol (5 mL) was stirred at 100° C. for 48 hunder carbon monoxide (3.2 Mpa). The mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by preparative TLC (petroleum ether: ethyl acetate=3:1, Rf=0.3)to give butyl4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate (50mg, 42%), used as is in the next step.

Step 5: 4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylicacid

To a solution of butyl4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate (50mg, 0.17 mmol) in tetrahydrofuran (4 mL)/water (2 mL) was added lithiumhydroxide monohydrate (50 mg, 1.2 mmol). The reaction mixture wasstirred at 30° C. for 12 h and subsequently concentrated under reducedpressure. The aqueous residue was diluted with water (10 mL) andadjusted to pH=5 by addition of hydrochloric acid (1 N). The resultingmixture was extracted with dichloromethane (3×10 mL). The combinedorganic layers were concentrated under reduced pressure to afford crude4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylic acid(25 mg, 62%) as a white solid, used in the next step without furtherpurification. LCMS R_(T)=0.867 min, m/z=245.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoroacetic acid over2.0 mins) retention time 0.867 min, ESI+ found [M+H]=245.1.

Step 6:(3,3-difluoroazetidin-1-yl)-(4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methanone

A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(19 mg, 0.10 mmol) 3,3-difluoroazetidine hydrochloride (12 mg, 0.09mmol), 1-hydroxybenzotriazole (13 mg, 0.10 mmol) and4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylic acid(20 mg, 0.08 mmol) in N,N-dimethylformamide (3 mL) was stirred at 28° C.for 15 h. The mixture was concentrated under reduced pressure and theresidue was purified by RP-HPLC(acetonitrile 25-55%/0.05% ammoniumhydroxide in water) to afford(3,3-difluoroazetidin-1-yl)-(4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methanone(6.4 mg, 24%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.38 (m, 5H),6.24 (s, 1H), 5.82 (s, 1H), 4.95-4.88 (m, 2H), 4.48-4.42 (m, 2H),4.45-4.37 (m, 2H), 4.29-4.17 (m, 2H). LCMS R_(T)=1.729 min, m/z=320.1[M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3mins) retention time 1.729 min, ESI+ found [M+H]=320.1.

Example 14, Method #14

(3,3-difluoroazetidin-1-yl)-[7-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Step 1: 4-chloro-2-(2-fluorophenyl)butanoic acid

To a stirred solution of 2-(2-fluorophenyl)acetic acid (10.0 g, 64.9mmol) in tetrahydrofuran (300 mL) was added n-butyllithium (2.5 M inhexanes, 51.9 mL, 129.8 mmol) dropwise at −78° C. The resulting mixturewas stirred for 20 min at −78° C. and 1 h at 0° C., andsubsequently-bromo-2-chloroethane (5.59 mL, 64.9 mmol) was added. Thereaction mixture was allowed to warm to 25° C. over 15 h and quenched byaddition of hydrochloric acid (1 N, 100 mL). The mixture was extractedwith ethyl acetate (3×150 mL). The combined organic layers were washedwith brine (200 mL) and concentrated under reduced pressure. The residuewas purified by column chromatography (silica gel, 100-200 mesh,dichloromethane) to afford 4-chloro-2-(2-fluorophenyl)butanoic acid (9.5g, 68%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 7.41-7.24 (m, 2H),7.21-6.98 (m, 2H), 4.18-4.08 (m, 1H), 3.63-3.55 (m, 1H), 3.46-3.38 (m,1H), 2.58-2.47 (m, 1H), 2.25-2.10 (m, 1H).

Step 2: 4-chloro-2-(2-fluorophenyl)butanoyl chloride

To a mixture of 4-chloro-2-(2-fluorophenyl)butanoic acid (1.0 g, 4.62mmol) in dichloromethane (6 mL), one drop N,N-dimethylformamide andoxalyl chloride (1.97 mL, 23.2 mmol) was added dropwise. The mixture wasstirred at 25° C. for 1.5 h and concentrated under reduced pressure(below 30° C.) to afford crude 4-chloro-2-(2-fluorophenyl)butanoylchloride (1.08 g, 99%) as a yellow oil, use in the next step withoutfurther purification.

Step 3: tert-butyl2-(4-chloro-2-(2-fluorophenyl)butanoyl)hydrazinecarboxylate

To a solution of triethylamine (0.81 mL, 13.78 mmol) and tert-butylhydrazinecarboxylate (1.21 g, 9.19 mmol) in tetrahydrofuran (30 mL) wasadded 4-chloro-2-(2-fluorophenyl)butanoyl chloride (1.08 g, 4.59 mmol)in tetrahydrofuran (3 mL) at 0° C. The resulting mixture was stirred at0° C. for 2 h and subsequently diluted with water (150 mL) and ethylacetate (200 mL). The separated organic layer was washed with 1 Nhydrochloric acid (2×30 mL) and brine (30 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 100-200 mesh, 0 to 4%methanol in dichloromethane) to afford tert-butyl2-(4-chloro-2-(2-fluorophenyl)butanoyl)hydrazinecarboxylate (1.07 g,70%) as a yellow oil.

LCMS R_(T)=0.741 min, m/z=230.8 [M−100+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5mins) retention time 0.741 min, ESI+ found [M−100+H]=230.8.

Step 4: 4-chloro-2-(2-fluorophenyl)butanehydrazide

To s solution of tert-butylN-[[4-chloro-2-(2-fluorophenyl)butanoyl]amino]carbamate (1.07 g, 3.2mmol) in ethyl acetate (2.0 mL) was added hydrochloric acid (4.0 N inethyl acetate, 10.0 mL, 40.0 mmol). The mixture was stirred for 1.5 hand concentrated under reduced pressure. The residue was diluted withethyl acetate (60 mL), washed with saturated aqueous sodium bicarbonate(20 mL), brine (20 mL), dried over sodium sulfate and concentrated underreduced pressure to afford crude4-chloro-2-(2-fluorophenyl)butanehydrazide (740 mg, 100%) as a yellowoil. LCMS R_(T)=0.591 min, m/z=230.8 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5mins) retention time 0.591 min, ESI+ found [M+H]=230.8.

Step 5: (Z)-ethyl2-amino-2-(2-(4-chloro-2-(2-fluorophenyl)butanoyl)hydrazono)acetate

To a solution of 4-chloro-2-(2-fluorophenyl)butanehydrazide (746 mg,3.23 mmol) in ethanol (10 mL) was added ethyl 2-ethoxy-2-imino-acetate(469 mg, 3.23 mmol). The mixture was stirred at 25° C. for 2 h and thenfiltered. The solid was dried in vacuo to afford crude (Z)-ethyl2-amino-2-(2-(4-chloro-2-(2-fluorophenyl)butanoyl)hydrazono)acetate (650mg, 61%) as a white solid, used in the next step without any furtherpurification. LCMS R_(T)=0.786 min, m/z=329.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5mins) retention time 0.786 min, ESI+ found [M+H]=329.9.

Step 6: ethyl5-(3-chloro-1-(2-fluorophenyl)propyl)-1H-1,2,4-triazole-3-carboxylate

A mixture of ethyl(2E)-2-amino-2-[[4-chloro-2-(2-fluorophenyl)butanoyl]hydrazono]acetate(650 mg, 1.97 mmol) and phosphorus oxychloride (8.0 mL, 85.57 mmol) wasstirred at 120° C. for 1.5 h and subsequently quenched by addition ofwater (50 mL). The resulting mixture was extracted with ethyl acetate(2×50 mL). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure to afford crude ethyl5-[3-chloro-1-(2-fluorophenyl)propyl]-1H-1,2,4-triazole-3-carboxylate(614 mg, 100%) as a colorless oil, used in the next step without furtherpurification. LCMS R_(T)=0.716 min, m/z=311.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5mins) retention time 0.716 min, ESI+ found [M+H]=311.9.

Step 7: ethyl7-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

To a solution of ethyl5-[3-chloro-1-(2-fluorophenyl)propyl]-1H-1,2,4-triazole-3-carboxylate(614 mg, 1.97 mmol) in N,N-dimethylformamide (4 mL) was added potassiumcarbonate (272 mg, 1.97 mmol). The reaction mixture was stirred at 25°C. for 15 h and filtered. The filtrate was concentrated under reducedpressure and the residue was purified by column chromatography (silicagel, 100-200 mesh, 0 to 3% methanol in dichloromethane) to afford ethyl7-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(450 mg, 83%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 7.41-7.25 (m,2H), 7.22-7.08 (m, 2H), 4.76-4.72 (m, 1H), 4.49-4.28 (m, 4H), 3.38-3.33(m, 1H), 2.84-2.66 (m, 1H), 1.38 (t, J=7.2 Hz, 3H).

Step 8:7-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid

A mixture of ethyl7-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(450 mg, 1.63 mmol) and lithium hydroxide monohydrate (141 mg, 3.37mmol) in tetrahydrofuran (30 mL)/water (7 mL) was stirred at 25° C. for2 h and concentrated under reduced pressure. The aqueous residue wasdiluted with water (10 mL) and adjusted to pH=5 by addition of 1N HCl.The resulting mixture was extracted with dichloromethane (4×50 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure to afford crude7-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (200 mg, 50%), used in the next step without further purification.LCMS R_(T)=0.658 min, m/z=247.9 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoroacetic acid over 1.5mins) retention time 0.658 min, ESI+ found [M+H]=247.9.

Step 9: 3-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole

A mixture of7-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (40 mg, 0.16 mmol), 3,3-difluoroazetidine hydrochloride (21 mg,0.16 mmol), 1-hydroxybenzotriazole (22 mg, 0.16 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (31 mg, 0.16mmol) in N,N-dimethylformamide (4 mL) was stirred at 25° C. for 2 h. Themixture was concentrated under reduced pressure and the residue waspurified by RP-HPLC (acetonitrile 25-55%/0.05% ammonium hydroxide inwater) to afford(3,3-difluoroazetidin-1-yl)-[7-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(11.1 mg, 21%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.47-7.23 (m,2H), 7.21-6.94 (m, 2H), 5.02-4.91 (m, 2H), 4.78-4.68 (m, 1H), 4.50 (t,J=12.0 Hz, 2H), 4.44-4.37 (m, 1H), 4.33-4.18 (m, 1H), 3.40-3.32 (m, 1H),2.74-2.63 (m, 1H). LCMS R_(T)=1.626 min, m/z=323.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.05% ammonium bicarbonate over 3mins) retention time 1.626 min, ESI+ found [M+H]=323.1.

Example 15, SFC 2

(3,3-difluoroazetidin-1-yl)-[(7S)-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanonewas prepared according to Method #4 and the following SFC purification(5 mg, 38% yield).

Purification:

SFC condition: Column: Chiralpak IG 150×21.2 mm I.D., Mobile phase: A:CO2 B:Methanol (0.1% NH40H) Isocratic: 25%: 70 mF/min Columntemperature: 40° C.

Analytical: Isocratic 20% MeOH, UV Wavelength: PDA Single 220.0 nm,Column: Chiralcel OX, Run Time: 2.5 Minutes, Co-Solvent: MeOH w/0.1%NH40H, ColumnTemp: 40.0

Example 16, Method #16

Step 1:(3,3-difluoroazetidin-1-yl)-(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

To a solution of5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid(25.0 mg, 0.109 mmol) in N,N-dimethylformamide (1.09 mL) was added 3,3difluoroazetidine (9.89 mg, 0.076 mmol), trimethylamine (0.07 mL, 0.436mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (94.0 mg, 0.24 mmol). The reaction mixturewas stirred at R_(T) for 16 h. The crude mixture was evaporated underreduced pressure and purified by RP-HPLC affording(3,3-difluoroazetidin-1-yl)-(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone (21.1 mg, 64%) as a white powder:1H NMR (400 MHz, DMSO-d6) δ 7.45-7.33 (m, 3H), 7.26-7.17 (m, 2H),5.66-5.54 (m, 1H), 4.85 (m, 2H), 4.45 (t, J=12.6 Hz, 2H), 3.24-3.14 (m,2H), 3.14-3.05 (m, 1H), 2.99 (m, 1H). LC-MS R_(T)=4.26 min, m/z=305.11(M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.26 min, ESI+ found [M+H]=305.1

Example 17

(3-methoxyazetidin-1-yl)-(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Method A (18.4 mg, 56% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.49-7.29 (m, 3H), 7.26-7.15 (m, 2H),5.64-5.51 (m, 1H), 4.67-4.52 (m, 1H), 4.23-4.19 (m, 2H), 4.20-4.15 (m,1H), 3.87-3.73 (m, 1H), 3.21 (s, 3H), 3.13-3.03 (m, 2H), 3.03-2.93 (m,2H). LC-MS R_(T)=3.94 min, m/z=299.14 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 3.94 min, ESI+ found [M+H]=299.1

Example 18

(3-fluoroazetidin-1-yl)-(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Method A (10.5 mg, 33% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.45-7.31 (m, 3H), 7.25-7.17 (m, 2H),5.64-5.54 (m, 1H), 4.86-4.68 (m, 1H), 4.55-4.27 (m, 2H), 4.14-3.98 (m,1H), 3.29-3.28 (m, 1H), 3.24-3.15 (m, 1H), 3.13-3.04 (m, 1H), 3.04-2.92(m, 1H), 2.60-2.52 (m, 1H). LC-MS R_(T)=4.01 min, m/z=287.12 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.01 min, ESI+ found [M+H]=287.1

Example 19

(3-methylazetidin-1-yl)-(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Method A (14.8 mg, 48% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.44-7.31 (m, 3H), 7.23-7.16 (m, 2H), 5.56(m, 1H), 4.58-4.44 (m, 1H), 4.18-4.06 (m, 1H), 4.02-3.91 (m, 1H),3.60-3.49 (m, 1H), 3.30-3.14 (m, 2H), 3.12-3.02 (m, 1H), 3.02-2.91 (m,1H), 2.74-2.63 (m, 1H), 1.22-1.15 (m, 3H). LC-MS R_(T)=4.36 min,m/z=283.14 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.36 min, ESI+ found [M+H]=283.1

Example 20

(3-fluoro-3-methyl-azetidin-1-yl)-(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Method A (12.3 mg, 38% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.43-7.32 (m, 3H), 7.26-7.17 (m, 2H), 5.58(dd, J=8.3, 5.7 Hz, 1H), 4.55-4.46 (m, 2H), 4.15-4.03 (m, 2H), 3.29-3.27(m, 1H), 3.17 (m, 1H), 3.13-3.03 (m, 1H), 3.03-2.93 (m, 1H), 1.64-1.50(m, 3H). LC-MS R_(T)=4.69 min, m/z=301.14 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.69 min, ESI+ found [M+H]=301.1

Example 21

(3-ethylazetidin-1-yl)-(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Method A (5.2 mg, 16% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.45-7.30 (m, 3H), 7.26-7.11 (m, 2H),5.63-5.50 (m, 1H), 4.55-4.43 (m, 1H), 4.13-3.94 (m, 2H), 3.64-3.53 (m,1H), 3.30-3.25 (m, 1H), 3.25-3.12 (m, 1H), 3.12-3.02 (m, 1H), 3.02-2.91(m, 1H), 2.58-2.52 (m, 1H), 1.60-1.49 (m, 2H), 0.87-0.79 (m, 3H). LC-MSR_(T)=5.03 min, m/z=297.16 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 5.03 min, ESI+ found [M+H]=297.1

Example 22

Azetidin-1-yl-[5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method A (4.0 mg, 17% yield).

LC-MS R_(T)=4.17 min, m/z=287.12 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.17 min, ESI+ found [M+H]=287.1

Example 23

(3,3-difluoroazetidin-1-yl)-[5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method A (16.0 mg, 62% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.44 (m, 1H), 7.33-7.11 (m, 3H), 5.80 (m,J=8.6, 5.6 Hz, 1H), 4.92-4.79 (m, 2H), 4.45 (m, 2H), 3.26-3.15 (m, 1H),3.13-2.94 (m, 2H), 2.69-2.54 (m, 1H). LC-MS R_(T)=4.64 min, m/z=323.1(M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.64 min, ESI+ found [M+H]=323.1

Example 24

(3-fluoroazetidin-1-yl)-[5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method A (14.0 mg, 57% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.51-7.35 (m, 1H), 7.33-7.12 (m, 3H), 5.78(dd, J=8.6, 5.6 Hz, 1H), 5.58-5.27 (m, 1H), 4.89-4.64 (m, 1H), 4.54-4.23(m, 2H), 4.15-3.93 (m, 1H), 3.25-3.13 (m, 1H), 3.13-2.94 (m, 2H),2.66-2.51 (m, 1H). LC-MS R_(T)=4.20 min, m/z=305.11 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.20 min, ESI+ found [M+H]=305.1

Example 25

N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Method A (11.8 mg, 38% yield).

Example 26

azetidin-1-yl-(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Method A (1.8 mg, 5% yield).

Example 27

N,N-dimethyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Method A (17.6 mg, 53% yield).

Example 28

2-azabicyclo[2.1.1]hexan-2-yl-(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone

Method A (21.2 mg, 59% yield).

Example 29

(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1-piperidyl)methanone

Method A (21.5 mg, 59% yield).

Example 30

(5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-pyrrolidin-1-yl-methanone

Method A (19.2 mg, 56% yield).

Example 31, SFC 3

(3,3-difluoroazetidin-1-yl)-[rac-(5S)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

(8.6 mg, 33% yield)

Purification:

SFC condition: Column: Chiralpak IC 150×30.0 mm I.D 5 uM., Mobile phase:A: CO2 B:Methanol (0.1% NH₄OH) Isocratic: 35%: 150 mL/min Columntemperature: 40° C.

Analytical

Peak 1, Isocratic 30% MeOH, UV Wavelength: PDA Single 254.0 nm, Column:Chiralpak IC, Rim Time: 2.5 Minutes, Co-Solvent: MeOH w/0.1% NH₄OH,ColumnTemp: 40.0° C.

Example 32, SFC 4

(3,3-difluoroazetidin-1-yl)-[rac-(5R)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

(7.8 mg, 30% yield)

Purification:

SFC condition: Column: Chiralpak IC 150×30.0 mm I.D 5 uM., Mobile phase:A: CO2 B:Methanol (0.1% NH40H) Isocratic: 35%: 150 mL/min Columntemperature: 40° C.

Analytical

Peak 2, Isocratic 30% MeOH, UV Wavelength: PDA Single 254.0 nm, Column:Chiralpak IC, Run Time: 2.5 Minutes, Co-Solvent: MeOH w/0.1% NH₄OH,ColumnTemp: 40.0° C. Examples 33-48: prepared according to one ofMethods #1-16 as described above. See also Table 1 below.

Example 49

Method #16

(3,3-difluoroazetidin-1-yl)-[(5S)-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Step 1: (S)-1-amino-5-(trifluoromethyl)pyrrolidin-2-one

To a solution of o-(diphenylphosphoryl)hydroxylamine (41.1 g, 176.4mmol) in N,N-dimethylformamide (900 mL) was added sodium hydride (60%,9.4 g, 235.1 mmol) at 25° C. The reaction mixture was stirred at 25° C.for 2 h and filtered. The filtrate was concentrated under reducedpressure to give (5S)-1-amino-5-(trifluoromethyl)pyrrolidin-2-one (19.5g, 99%) as a light yellow oil which was used in the next step withoutfurther purification.

Step 2: (S)-ethyl2-imino-2-((2-oxo-5-(trifluoromethyl)pyrrolidin-1-yl)amino)acetate

To a solution of (5S)-1-amino-5-(trifluoromethyl)pyrrolidin-2-one (30.0g, 178.4 mmol) in ethanol (280 mL) was added ethyl2-ethoxy-2-imino-acetate (38.9 g, 267.7 mmol). The reaction mixture wasstirred at 60° C. for 15 h and concentrated under reduced pressure toafford crude ethyl2-imino-2-[[(5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-1-yl]amino]acetateas a yellow oil (38.0 g, 80%) which was used in the next step withoutfurther purification.

Step 3: (S)-ethyl5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

A mixture of phosphorus oxychloride (284.2 g, 1853.6 mmol) and ethyl2-imino-2-[[(5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-1-yl]amino]acetate(37.5 g, 140.3 mmol) was heated at 110° C. for 1 h and concentratedunder reduced pressure. The residue was poured into water (50 mL) andadjusted to pH=10 by addition of saturated aqueous sodium bicarbonate.The resulting mixture was extracted with ethyl acetate (3×200 mL). Thecombined organic layers were dried and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel,100-200 mesh, 0 to 50% ethyl acetate in petroleum ether) to afford ethyl(5S)-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylateas a white solid (22.0 g, 63%).

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.508 min, ESI+ found [M+H]=250.0.

Step 4:(S)-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid

To a solution of ethyl(5S)-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate(8.0 g, 32.1 mmol) in tetrahydrofuran (80 mL) was added a solution oflithium hydroxide monohydrate (4.0 g, 96.3 mmol) in water (40 mL). Themixture was stirred at 25° C. for 16 h and concentrated under reducedpressure to remove the organic solvent. The residue was diluted withwater (30 mL) and washed with ethyl acetate (30 mL). The aqueous layerwas adjusted to pH=3 by addition of aqueous hydrochloric acid (4 N). Thecrude product was collected by filtration and dried in vacuo to give(5S)-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid as a white solid (6.0 g, 85%).

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 2mins) retention time 0.729 min, ESI+ found [M+H]=222.2.

Step 5:(3,3-difluoroazetidin-1-yl)-[(5S)-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

A mixture of(5S)-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (60 mg, 0.27 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (68 mg, 0.35mmol), 1-hydroxybenzotriazole (37 mg, 0.27 mmol), 3,3-difluoroazetidinehydrochloride (53 mg, 0.41 mmol) and N,N-diisopropylethylamine (70 mg,0.54 mmol) in N,N-dimethylformamide (3.5 mL) was stirred at 25° C. for 4h and concentrated under reduced pressure. The residue was purified byRP-HPLC (acetonitrile 25-55%/0.05% ammonia hydroxide in water) to afford(3,3-difluoroazetidin-1-yl)-[(5S)-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(33.8 mg, 42%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 5.30-5.26 (m,1H), 4.99-4.92 (m, 2H), 4.56-4.50 (m, 2H), 3.13-3.02 (m, 23), 2.88-2.87(m, 1H). LCMS R_(T)=1.294 min, m/z=297.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.1% ammonia water over 3.0 mins)retention time 1.294 min, ESI+ found [M+H]=297.1.

Example 50

Method 17

[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[3-(trifluoromethyl)azetidin-1-yl]methanone

A mixture ofcis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (25 mg, 0.10 mmol), 3-(trifluoromethyl)azetidine hydrochloride (18mg, 0.11 mmol), HATU (44 mg, 0.11 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.07 mL, 0.40 mmol) inN,N-dimethylformamide (0.5 mL) was stirred at 25° C. for 12 h. Isopropylacetate was added to the reaction mixture. The resulting solution waswashed with water (2×20 mL) and saturated aqueous sodium chloridesolution. The organic was dried over magnesium sulfate, filtered, andconcentrated. The residue was further purified by preparative RP-HPLC(20-60% acetonitrile in water+0.1% formic acid) to afford [rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[3-(trifluoromethyl)azetidin-1-yl]methanone(20.5 mg, 56%) as a white solid. ¹H NMR (400 MHz, DMSO-6?₆) δ 7.49-7.32(m, 3H), 7.29-7.16 (m, 2H), 6.21 (ddt, J=56.5, 7.2, 1.9 Hz, 1H), 5.70(ddd, J=9.0, 6.7, 3.0 Hz, 1H), 4.72 (dt, J=13.1, 9.7 Hz, 1H), 4.45 (td,J=9.7, 5.4 Hz, 1H), 4.29 (t, J=9.9 Hz, 1H), 4.02 (dd, J=10.7, 5.4 Hz,1H), 3.87-3.55 (m, 2H), 2.85-2.54 (m, 1H). LCMS R_(T)=4.59 min,m/z=355.1 [M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.59 min, ESI+ found [M+H]=355.1

Example 51

[3-(difluoromethyl)azetidin-1-yl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (12.9 mg, 38% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.49-7.32 (m, 3H), 7.27-7.11 (m, 2H),6.59-6.09 (m, 2H), 5.69 (ddd, J=8.9, 6.7, 3.0 Hz, 1H), 4.56 (q, J=9.0Hz, 1H), 4.38 (td, J=11.0, 5.6 Hz, 1H), 4.14 (t, J=9.7 Hz, 1H), 3.95(dd, J=10.5, 5.5 Hz, 1H), 3.72 (dddd, J=26.2, 15.5, 8.5, 7.1 Hz, 1H),3.24-3.05 (m, 1H), 2.79-2.58 (m, 1H). LCMS R_(T)=4.22 min, m/z=337.1[M+H]⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.22 min, ESI+ found [M+H]=337.1

Examples 52 and 53

[rac-(2R)-2-(difluoromethyl)azetidin-1-yl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone&[rac-(2S)-2-(difluoromethyl)azetidin-1-yl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[2-(difluoromethyl)azetidin-1-yl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanonewas prepared corresponding from 2-(difluoromethyl)azetidine2,2,2-trifluoroacetate andrac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid according to Method 17. The crude residue was further purified bychiral SFC (Chiralpak AD; 150×21.2 mm; 20% methanol isocratic elutionwith Carbon Dioxide) affording arbitrarily assigned two diastereomers asbelow:

[rac-(2R)-2-(difluoromethyl)azetidin-1-yl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(30.7 mg, 28.2%) as white solids[rac-(2S)-2-(difluoromethyl)azetidin-1-yl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(32.3 mg, 30.0%) as white solids

Analytical data for the first eluting diastereomer (arbitrarily assigned2R, 5S, 7S configuration): SFC R_(T) (Chiralpak AD, 15% methanol+0.1%ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 minmethod): 0.711 min, 100% purity, 100% ee: 1H NMR (400 MHz, DMSO-d6) δ7.47-7.32 (m, 3H), 7.28-7.18 (m, 2H), 6.80-6.08 (m, 2H), 5.70 (td,J=8.8, 7.7, 2.8 Hz, 1H), 5.18-4.62 (m, 1H), 4.39 (dt, J=9.1, 6.5 Hz,1H), 3.98 (dtd, J=38.7, 9.5, 6.0 Hz, 1H), 3.73 (dddd, J=26.1, 15.5, 8.5,7.1 Hz, 1H), 2.78-2.51 (m, 1H), 2.42 (dddd, J=15.6, 11.7, 8.5, 5.7 Hz,1H), 2.27 (dddd, J=11.5, 8.7, 6.1, 2.7 Hz, 1H). LCMS R_(T)=10.48 min,m/z=337.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 30 mins)retention time 10.48 min, ESI+ found [M+H]=337.1

Analytical data for the second eluting diastereomer (arbitrarilyassigned 2S, 5S, 7S configuration): SFC R_(T) (Chiralpak AD, 15%methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide,2.5 min method): 0.990 min, 99.4% purity, 98.8% ee: ¹H NMR (400 MHz,DMSO-d₆) δ 7.40 (dddd, J=10.6, 8.6, 6.7, 3.6 Hz, 3H), 7.31-7.16 (m, 2H),6.78-6.02 (m, 2H), 5.70 (ddd, J=8.8, 6.7, 2.8 Hz, 1H), 5.32-4.62 (m,1H), 4.38 (dd, J=8.5, 7.0 Hz, 1H), 4.11-3.84 (m, 1H), 3.73 (dddd,J=26.0, 15.4, 8.5, 7.1 Hz, 1H), 2.81-2.58 (m, 1H), 2.48-2.35 (m, 1H),2.34-2.17 (m, 1H).

LCMS R_(T)=10.53 min, m/z=337.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 30 mins)retention time 10.53 min, ESI+ found [M+H]=337.1

Example 54

(3,3-difluoropyrrolidin-1-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (63 mg, 89% yield)

The crude residue was further purified by chiral SFC (Whelko-01;150×21.2 mm; 45% methanol isocratic elution with Carbon Dioxide)affording arbitrarily assigned diastereomers(3,3-difluoropyrrolidin-1-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(8.0 mg, 31%) as white solids

Analytical data for the second eluting diastereomer (arbitrarilyassigned 5R, 7R configuration): SFC R_(T) (Whelk-O1 S,S, 40%methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide,2.5 min method): 1.311 min, 93% purity, 86% ee: ¹H NMR (400 MHz,DMSO-d₆) δ 7.53-7.33 (m, 3H), 7.24 (ddd, J=7.8, 3.7, 1.5 Hz, 2H), 6.22(ddd, J=56.5, 7.2, 1.9 Hz, 1H), 5.70 (td, J=8.0, 4.2 Hz, 1H), 4.22 (t,J=12.9 Hz, 1H), 4.05-3.96 (m, 1H), 3.91 (t, J=13.2 Hz, 1H), 3.85-3.61(m, 2H), 2.69 (ddt, J=26.8, 15.2, 2.4 Hz, 1H), 2.49-2.31 (m, 2H). LCMSR_(T)=4.42 min, m/z=337.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.42 min, ESI+ found [M+H]=337.1

Example 55

rac-(5S,7S)-7-fluoro-N-(2-methoxyethyl)-5-phenyl-N-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Method 17 (3.2 mg, 8% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.47-7.33 (m, 3H), 7.27-7.18 (m, 2H),6.36-6.03 (m, 1H), 5.68 (dddd, J=18.3, 15.5, 8.8, 3.7 Hz, 1H), 4.39 (qd,J=9.5, 6.4 Hz, 1H), 3.93-3.67 (m, 2H), 3.57-3.38 (m, 2H), 3.29-3.21 (m,3H), 2.78-2.61 (m, 1H), 1.39 (dd, J=6.6, 1.4 Hz, 1H), 1.11 (dd, J=12.5,6.6 Hz, 1H). LCMS R_(T)=4.89 min, m/z=387.2 (M+H)⁺.

LCMS (2 to 98% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.89 min, ESI+ found [M+H]=387.2

Example 56

rac-(5R,7R)—N-(2,2-difluoroethyl)-7-fluoro-N-(2-methoxyethyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Method 17 (10 mg, 27% yield)

The crude residue was further purified by achiral SFC (Pyridyl Amide;150×21.2 mm; 5-60% methanol elution with Carbon Dioxide) affordingarbitrarily assigned diastereomersrac-(5R,7R)—N-(2,2-difluoroethyl)-7-fluoro-N-(2-methoxyethyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 7.56-7.05 (m, 5H), 6.50-5.95 (m, 2H), 5.69(ddd, J=8.4, 6.7, 3.0 Hz, 1H), 4.14 (td, J=14.6, 4.0 Hz, 1H), 3.91 (tdd,J=14.8, 4.1, 2.7 Hz, 1H), 3.83-3.61 (m, 3H), 3.49 (dt, J=38.7, 5.6 Hz,2H), 3.11 (s, 3H), 2.69 (ddtd, J=23.7, 13.9, 3.3, 1.8 Hz, 1H). LCMSR_(T)=4.57 min, m/z=369.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.57 min, ESI+ found [M+H]=369.2

Example 57

rac-(5S,7S)-7-fluoro-N-(oxetan-3-yl)-5-phenyl-N-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Method 17 (2 mg, 4% yield)

NO NMR

LCMS R_(T)=4.51 min, m/z=385.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.51 min, ESI+ found [M+H]=385.1

Example 58

rac-(5S,7S)—N-cyclopropyl-N-(2,2-difluoroethyl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Method 17 (33.9 mg, 96% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.47-7.32 (m, 3H), 7.26-7.18 (m, 2H),6.56-6.03 (m, 2H), 5.80-5.62 (m, 1H), 4.24-3.55 (m, 4H), 2.92 (s, 1H),2.80-2.50 (m, 1H), 0.91-0.35 (m, 3H). LCMS R_(T)=4.68 min, m/z=351.1(M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.68 min, ESI+ found [M+H]=351.1

Example 59

rac-(5S,7S)—N-cyclopropyl-7-fluoro-5-phenyl-N-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Method 17 (3.5 mg, 9% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.54-7.25 (m, 3H), 7.33-7.10 (m, 2H), 6.23(ddd, J=56.6, 7.1, 1.7 Hz, 1H), 5.84-5.60 (m, 1H), 4.95-4.19 (m, 2H),3.75 (ddt, J=26.2, 15.5, 7.8 Hz, 1H), 2.92 (s, 1H), 2.84-2.45 (m, 1H),0.97-0.43 (m, 4H). LCMS R_(T)=5.01 min, m/z=369.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 5.01 min, ESI+ found [M+H]=369.1

Example 60

[2-(difluoromethyl)azetidin-1-yl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (25.3 mg, 74% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.53-7.31 (m, 3H), 7.23 (td, J=7.9, 1.9 Hz,2H), 6.63-6.07 (m, 2H), 5.70 (ddd, J=8.8, 5.4, 2.8 Hz, 1H), 5.32-4.61(m, 1H), 4.39 (dp, J=9.6, 3.4 Hz, 1H), 4.08-3.87 (m, 1H), 3.73 (dddd,J=26.1, 15.5, 8.5, 7.2 Hz, 1H), 2.78-2.61 (m, 1H), 2.51-2.34 (m, 1H),2.33-2.21 (m, 1H). LCMS R_(T)=4.46 min, m/z=337.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.46 min, ESI+ found [M+H]=337.1

Example 61

rac-(5S,7S)—N,N-dicyclopropyl-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Method 17 (27.2 mg, 82% yield)

1H NMR (400 MHz, DMSO-d6) δ 7.46-7.30 (m, 3H), 7.23-7.15 (m, 2H), 6.20(ddd, J=56.7, 7.1, 1.7 Hz, 1H), 5.68 (ddd, J=8.8, 6.7, 2.8 Hz, 1H), 3.73(dddd, J=26.6, 15.5, 8.5, 7.1 Hz, 1H), 2.76-2.51 (m, 3H), 0.60 (m, 8H).LCMS R_(T)=4.40 min, m/z=327.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.40 min, ESI+ found [M+H]=327.2

Example 62

(7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (39.1 mg, 99% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.52-7.31 (m, 4H), 7.26 (dt, J=8.7, 3.1 Hz,2H), 6.42-5.94 (m, 2H), 5.71 (t, J=6.6 Hz, 1H), 5.11-4.91 (m, 1H),5.05-4.71 (m, 1H), 4.37 (dq, J=13.1, 6.6 Hz, 1H), 4.26-4.06 (m, 1H),4.02-3.62 (m, 2H), 2.87-2.57 (m, 1H), 1.50-1.21 (m, 3H). LCMS R_(T)=4.05min, m/z=367.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.05 min, ESI+ found [M+H]=367.2

Example 63

(2-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (28.7 mg, 77% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.52-7.33 (m, 3H), 7.26 (ddd, J=8.0, 3.5,1.5 Hz, 2H), 6.23 (ddt, J=56.5, 7.2, 2.3 Hz, 1H), 5.78-5.63 (m, 1H),4.94 (s, 1H), 4.81 (d, J=2.8 Hz, 1H), 4.19-4.01 (m, 4H), 3.74 (ddt,J=25.8, 15.5, 7.8 Hz, 1H), 2.79-2.62 (m, 1H), 2.12 (d, J=8.8 Hz, 3H).LCMS R_(T)=4.01 min, m/z=367.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.01 min, ESI+ found [M+H]=367.2

Examples 64 and 65

[rac-(2S)-2-(difluoromethyl)pyrrolidin-1-yl]-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone&[rac-(2R)-2-(difluoromethyl)pyrrolidin-1-yl]-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

[2-(difluoromethyl)pyrrolidin-1-yl]-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanonewas prepared according to Method 17. The crude residue was furtherpurified by chiral SFC (Whelko-01; 150×21.2 mm; 45% methanol isocraticelution with Carbon Dioxide) affording arbitrarily assigned twodiastereomers as below:

[rac-(2S)-2-(difluoromethyl)pyrrolidin-1-yl]-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(10.9 mg, 15%) as white solids

[rac-(2R)-2-(difluoromethyl)pyrrolidin-1-yl]-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(9.5 mg, 13%) as white solids

Analytical data for the fourth eluting diastereomer (arbitrarilyassigned 2S, 5R, 7R configuration): SFC R_(T) (Whelk-O1 S,S, 35%methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide,2.5 min method): 1.559 min, 100% purity, 100% ee: ¹H NMR (400 MHz,DMSO-d₆) δ 7.47-7.33 (m, 3H), 7.23 (ddd, J=7A, 3.8, 1.5 Hz, 2H),6.59-5.98 (m, 2H), 5.70 (ddt, J=9.4, 6.5, 2.9 Hz, 1H), 5.16-4.43 (m,1H), 3.86-3.62 (m, 3H), 2.77-2.61 (m, 1H), 2.16-1.79 (m, 4H). LCMSR_(T)=4.72 min, m/z=351.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.72 min, ESI+ found [M+H]=351.1

Analytical data for the third eluting diastereomer (arbitrarily assigned2R, 5R, 7R configuration): SFC R_(T) (Whelk-O1 S,S, 35% methanol+0.1%ammonium hydroxide isocratic elution with Carbon Dioxide, 2.5 minmethod): 1.272 min, 100% purity, 100% ee: ¹H NMR (400 MHz, DMSO-d₆) δ7.47-7.33 (m, 3H), 7.22 (tt, J=8.5, 1.6 Hz, 2H), 6.51-5.99 (m, 2H), 5.70(ddd, J=9.5, 7.0, 3.0 Hz, 1H), 5.12-4.38 (m, 1H), 3.88-3.61 (m, 3H),2.77-2.60 (m, 1H), 2.16-1.78 (m, 4H). LCMS R_(T)=4.71 min, m/z=351.2(M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.71 min, ESI+ found [M+H]=351.2

Example 66

6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone

6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanonewas prepared according to Method 17. The crude residue was furtherpurified by chiral SFC (Chiralpak IC; 150×21.2 mm; 50% methanolisocratic elution with Carbon Dioxide) affording arbitrarily assigneddiastereomers as below:6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(7.5 mg, 28%) as white solids

Analytical data for this second eluting diastereomer (arbitrarilyassigned 5R, 7R configuration): SFC R_(T) (Chiralpak IC, 40%methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide,2.5 min method): 1.583 min, 100% purity, 100% ee: ¹H NMR (400 MHz,DMSO-d₆) δ 7.48-7.34 (m, 4H), 7.30-7.23 (m, 2H), 6.39-6.00 (m, 2H), 5.70(dtd, J=8.9, 6.2, 2.9 Hz, 1H), 5.02 (s, 1H), 4.88 (d, J=2.2 Hz, 1H),4.27-4.00 (m, 4H), 3.75 (dddd, J=26.3, 14.6, 8.9, 7.3 Hz, 1H), 2.71(ddd, J=26.7, 15.3, 2.6 Hz, 1H). LCMS R_(T)=3.84 min, m/z=353.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 3.84 min, ESI+ found [M+H]=353.2

Example 67

6,8-dihydro-5H-1,7-naphthyridin-7-yl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

6,8-dihydro-5H-1,7-naphthyridin-7-yl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanonewas prepared according to Method 17. The crude residue was furtherpurified by chiral SFC (Whelko-01; 150×21.2 mm; 50% methanol isocraticelution with Carbon Dioxide) affording arbitrarily assigneddiastereomers as below:

6,8-dihydro-5H-1,7-naphthyridin-7-yl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(6.8 mg, 25%) as white solids

Analytical data for this second eluting diastereomer (arbitrarilyassigned 5R, 7R configuration): SFC R_(T) (Whelk-O1 S,S, 45%methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide,2.5 min method): 2.053 min, 100% purity, 100% ee: ¹H NMR (400 MHz,DMSO-d6) δ 8.38 (ddd, J=25.5, 4.7, 1.6 Hz, 1H), 7.61 (ddd, J=7.8, 4.6,1.6 Hz, 1H), 7.48-7.33 (m, 3H), 7.30-7.19 (m, 3H), 6.37-6.08 (m, 1H),5.70 (dtd, J=8.5, 5.6, 3.0 Hz, 1H), 4.83 (d, J=29.7 Hz, 2H), 4.03-3.84(m, 2H), 3.84-3.63 (m, 1H), 2.89 (t, J=5.9 Hz, 2H), 2.79-2.62 (m, 1H).LCMS R_(T)=3.44 min, m/z=364.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 3.44 min, ESI+ found [M+H]=364.2

Example 68

6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone

Method 17 (23.0 mg, 65% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.58-7.26 (m, 3H), 7.38-7.11 (m, 2H), 7.12(d, J=1.2 Hz, 1H), 6.89 (dd, J=14.9, 1.3 Hz, 1H), 6.23 (ddd, J=56.6,7.2, 1.9 Hz, 1H), 5.70 (tt, J=73, 3.4 Hz, 1H), 4.87 (d, J=63.2 Hz, 2H),4.09 (dt, J=12.6, 3.7 Hz, 4H), 3.91-3.58 (m, 1H), 2.71 (ddt, J=26.7,15.2, 2.4 Hz, 1H). LCMS R_(T)=2.44 min, m/z=353.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 2.44 min, ESI+ found [M+H]=353.2

Example 69

6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (25.1 mg, 65% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.55-7.26 (m, 4H), 7.26 (dd, J=7.4, 2.9 Hz,2H), 6.42-5.97 (m, 2H), 5.70 (ddt, J=9.2, 5.7, 2.9 Hz, 1H), 5.02 (s,1H), 4.88 (d, J=1.9 Hz, 1H), 4.29-4.00 (m, 4H), 3.75 (ddt, J=25.8, 15.5,7.8 Hz, 1H), 2.82-2.61 (m, 1H). LCMS R_(T)=3.83 min, m/z=353.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 3.83 min, ESI+ found [M+H]=353.2

Example 70

[rac-(2R,4S)-4-fluoro-2-methyl-pyrrolidin-1-yl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone{arbitrarily assigned (2R, 4S), (5S, 7S) configuration}

Method 17 (22.7 mg, 68% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.54-7.25 (m, 3H), 7.23 (tt, J=6.6, 2.0 Hz,2H), 6.41-6.03 (m, 1H), 5.69 (td, J=8.2, 7.6, 2.9 Hz, 1H), 5.33 (dt,J=53.6, 4.5 Hz, 1H), 4.54 (dp, J=126.8, 7.2, 6.8 Hz, 1H), 4.22-3.62 (m,3H), 2.84-2.59 (m, 1H), 2.46-2.12 (m, 1H), 1.96 (ddd, J=28.5, 19.6, 14.5Hz, 1H), 1.40-1.02 (m, 3H). LCMS R_(T)=4.36 min, m/z=333.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.36 min, ESI+ found [M+H]=333.2

Example 71

[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone(arbitrarily assigned 2R, 5S, 7S) configuration)

Method 17 (12.5 mg, 37% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.59-7.31 (m, 3H), 7.28-7.11 (m, 2H), 6.20(ddt, J=56.6, 7.2, 2.0 Hz, 1H), 5.68 (ddt, J=8.6, 5.7, 2.7 Hz, 1H),4.86-4.67 (m, 1H), 4.45 (s, 1H), 4.12 (dd, J=7.1, 3.8 Hz, 1H), 3.90-3.41(m, 3H), 3.31 (s, 2H), 2.84-2.52 (m, 1H), 2.07-1.65 (m, 3H). LCMSR_(T)=3.65 min, m/z=331.2 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 3.65 min, ESI+ found [M+H]=331.2

Example 72

[4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(arbitrarily assigned 5S, 7S configuration)

Method 17 (24.5 mg, 66% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.47-7.32 (m, 3H), 7.29-7.18 (m, 2H), 6.22(dddd, J=56.5, 7.2, 3.5, 1.9 Hz, 1H), 5.74-5.65 (m, 1H), 5.04 (t, J=5.5Hz, 1H), 4.87 (s, 1H), 4.48-4.29 (m, 2H), 4.10 (ddt, J=31.6, 21.2, 10.7Hz, 1H), 3.86-3.63 (m, 1H), 3.59 (q, J=5.1 Hz, 1H), 3.43-3.17 (m, 2H),2.78-2.61 (m, 1H). LCMS R_(T)=4.06 min, m/z=366.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.06 min, ESI+ found [M+H]=366.9

Example 73

[rac-(2S)-4,4-difluoro-2-(fluoromethyl)pyrrolidin-1-yl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(arbitrarily assigned 2S, 5S, 7S configuration)

Method 17 (22.3 mg, 60% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.41 (dddd, J=12.0, 7.2, 5.9, 2.2 Hz, 3H),7.29-7.19 (m, 2H), 6.22 (dddd, J=56.5, 7.2, 3.3, 1.9 Hz, 1H), 5.70 (ddt,J=8.8, 5.7, 2.7 Hz, 1H), 5.19 (s, 1H), 4.75-4.51 (m, 2H), 4.55-4.32 (m,1H), 4.29-4.06 (m, 1H), 3.92-3.64 (m, 1H), 2.96-2.61 (m, 2H), 2.50-2.37(m, 1H). LCMS R_(T)=4.75 min, m/z=368.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.75 min, ESI+ found [M+H]=368.9

Example 74

6,8-dihydro-5H-1,7-naphthyridin-7-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(arbitrarily assigned 5S, 7S configuration)

Method 17 (27.3 mg, 74% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.38 (dddd, J=25.7, 4.7, 1.7 Hz, 1H), 7.61(ddd, J=7.7, 4.8, 1.6 Hz, 1H), 7.48-7.32 (m, 3H), 7.30-7.19 (m, 3H),6.37-6.11 (m, 1H), 5.75-5.65 (m, 1H), 4.83 (d, J=29.7 Hz, 2H), 3.99-3.80(m, 2H), 3.85-3.65 (m, 1H), 2.95-2.85 (m, 2H), 2.79-2.63 (m, 1H).

LCMS R_(T)=3.44 min, m/z=363.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 3.44 min, ESI+ found [M+H]=363.9

Example 75

3,4-dihydro-1H-2,6-naphthyridin-2-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(arbitrarily assigned 5S, 7S configuration)

Method 17 (20.3 mg, 55% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.43-8.29 (m, 2H), 7.48-7.33 (m, 3H),7.32-6.99 (m, 3H), 6.23 (ddt, J=56.6, 7.6, 2.5 Hz, 1H), 5.70 (qd, J=8.1,3.1 Hz, 1H), 4.92-4.76 (m, 2H), 4.03-3.64 (m, 3H), 2.88 (t, J=5.9 Hz,2H), 2.79-2.63 (m, 1H). LCMS R_(T)=2.65 min, m/z=363.9 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 2.65 min, ESI+ found [M+H]=363.9

Example 76

3,4-dihydro-1H-isoquinolin-2-yl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

3,4-dihydro-1H-isoquinolin-2-yl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanonewas prepared according to Method 17. The crude residue was furtherpurified by chiral SFC (Whelko-01; 150×21.2 mm; 50% methanol isocraticelution with Carbon Dioxide) affording arbitrarily assigneddiastereomers as below:3,4-dihydro-1H-isoquinolin-2-yl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(9.6 mg, 36%) as white solids

Analytical data for this second eluting diastereomer (arbitrarilyassigned 5R, 7R configuration): SFC R_(T) (Whelk-O1 S,S, 45%methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide,2.5 min method): 1.752 min, 100% purity, 100% ee: ¹H NMR (400 MHz,DMSO-d6) δ 7.48-7.33 (m, 3H), 7.30-6.97 (m, 6H), 6.23 (ddd, J=56.6, 7.2,1.9 Hz, 1H), 5.70 (dq, J=7.1, 3.2 Hz, 1H), 4.78 (s, 2H), 3.92-3.65 (m,3H), 2.87 (q, J=6.4 Hz, 2H), 2.79-2.62 (m, 1H). LCMS R_(T)=5.03 min,m/z=363.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 5.03 min, ESI+ found [M+H]=363.1

Example 77

(3-phenoxypyrrolidin-1-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(arbitrarily assigned 5S, 7S configuration)

Method 17 (31.6 mg, 67% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.47-7.33 (m, 3H), 7.38-7.15 (m, 4H),7.01-6.89 (m, 3H), 6.35-6.04 (m, 1H), 5.75-5.62 (m, 1H), 5.09 (qd,J=4.5, 2.4 Hz, 1H), 4.07-3.89 (m, 1H), 3.84-3.51 (m, 4H), 2.77-2.58 (m,1H), 2.29-2.05 (m, 2H). LCMS R_(T)=5.08 min, m/z=393.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 5.08 min, ESI+ found [M+H]=393.1

Example 78

[2-(difluoromethyl)pyrrolidin-1-yl]-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(arbitrarily assigned 5S, 7S configuration)

Method 17 (4.1 mg, 10% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.57-7.23 (m, 3H), 7.22 (ddt, J=8.5, 5.3,1.5 Hz, 2H), 6.68-5.90 (m, 2H), 5.70 (td, J=7.7, 6.5, 2.8 Hz, 1H),4.69-4.33 (m, 1H), 3.96-3.54 (m, 3H), 2.87-2.50 (m, 1H), 2.25-1.63 (m,4H). LCMS R_(T)=4.71 min, m/z=351.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.71 min, ESI+ found [M+H]=351.1

Example 79

(3,3-difluoro-1-piperidyl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (30.9 mg, 69% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.47-7.28 (m, 3H), 7.28-7.19 (m, 2H),6.37-6.07 (m, 1H), 5.74-5.63 (m, 1H), 4.07 (t, J=11.8 Hz, 1H), 3.96 (t,J=12.0 Hz, 1H), 3.83-3.58 (m, 3H), 2.70 (dddd, J=26.7, 15.2, 3.1, 1.9Hz, 1H), 2.09 (qt, J=13.1, 6.7 Hz, 2H), 1.70 (td, J=6.8, 3.9 Hz, 2H).LCMS R_(T)=4.50 min, m/z=351.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.50 min, ESI+ found [M+H]=351.1

Example 80

6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidin-4-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone

Method 17 (24.6 mg, 69% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.48-7.33 (m, 4H), 7.31-7.23 (m, 2H), 6.64(s, 1H), 6.24 (ddd, J=56.5, 7.1, 1.9 Hz, 1H), 5.71 (ddd, J=8.6, 6.7, 3.1Hz, 1H), 4.16 (t, J=6.1 Hz, 2H), 4.02 (tq, J=12.9, 7.3, 6.5 Hz, 2H),3.76 (dddd, J=25.7, 15.4, 8.5, 7.2 Hz, 1H), 2.80-2.63 (m, 1H), 2.14 (p,J=6.0 Hz, 2H). LCMS R_(T)=3.97 min, m/z=353.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 3.97 min, ESI+ found [M+H]=353.1

Example 81

[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[7-(trifluoromethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidin-4-yl]methanone

Method 17 (16.1 mg, 36% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (s, 1H), 7.56-7.26 (m, 3H), 7.38-7.16(m, 2H), 6.58 (s, 1H), 6.40-6.07 (m, 1H), 5.73 (ddt, J=9.4, 6.1, 2.9 Hz,1H), 5.35 (q, J=7.2, 6.3 Hz, 1H), 4.19 (t, J=15.5 Hz, 1H), 4.13-3.86 (m,1H), 3.76 (dddd, J=25.9, 15.5, 8.0, 6.9 Hz, 1H), 2.88-2.60 (m, 1H), 2.42(dh, J=14.9, 4.8 Hz, 2H). LCMS R_(T)=4.71 min, m/z=421.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.71 min, ESI+ found [M+H]=421.1

Example 82

[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]methanone(arbitrarily assigned 2S, 5S, 7S configuration)

Method 17 (32.2 mg, 72% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.41 (dtd, J=12.2, 6.8, 2.3 Hz, 3H),7.28-7.14 (m, 2H), 6.36-6.05 (m, 1H), 5.76-5.67 (m, 1H), 5.04 (td,J=8.4, 4.2 Hz, 1H), 3.89-3.64 (m, 3H), 2.69 (ddt, J=27.3, 18.9, 2.9 Hz,1H), 2.18-2.08 (m, 1H), 2.10-1.90 (m, 3H). LCMS R_(T)=4.94 min,m/z=369.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.94 min, ESI+ found [M+H]=369.1

Example 83

[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]methanone(arbitrarily assigned 2R, 5S, 7S configuration)

Method 17 (30.2 mg, 67% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.40 (ddtt, J=12.4, 9.5, 7.2, 2.1 Hz, 3H),7.30-7.11 (m, 2H), 6.38-6.09 (m, 1H), 5.80-5.65 (m, 1H), 5.04 (td,J=8.3, 4.1 Hz, 1H), 3.92-3.48 (m, 3H), 2.78-2.61 (m, 1H), 2.18-2.08 (m,1H), 2.06-1.78 (m, 3H). LCMS R_(T)=4.94 min, m/z=369.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.94 min, ESI+ found [M+H]=369.1

Example 84

[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[2-(trifluoromethyl)pyrrolidin-1-yl]methanone

Method 17 (33.9 mg, 52% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.49-7.31 (m, 3H), 7.28-7.14 (m, 2H),6.36-6.10 (m, 1H), 5.82-5.63 (m, 1H), 5.11-4.98 (m, 1H), 3.89-3.49 (m,3H), 2.78-2.61 (m, 1H), 2.18-2.08 (m, 1H), 2.06-1.90 (m, 3H). LCMSR_(T)=4.94 min, m/z=369.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.94 min, ESI+ found [M+H]=369.1

Examples 85 and 86

[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(2S,3R)-2-methyl-3-(trifluoromethyl)pyrrolidin-1-yl]methanone&[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(2S,3S)-2-methyl-3-(trifluoromethyl)pyrrolidin-1-yl]methanone

[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[2-methyl-3-(trifluoromethyl)pyrrolidin-1-yl]methanonewas prepared according to Method 17. The crude residue was furtherpurified by chiral SFC (Whelko-01; 150×21.2 mm; 40% methanol+0.1%ammonium hydroxide isocratic elution with Carbon Dioxide) affordingarbitrarily assigned two diastereomers as below:

[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(2S,3R)-2-methyl-3-(trifluoromethyl)pyrrolidin-1-yl]methanone(1.9 mg, 4%) as white solids

[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-[rac-(2S,3S)-2-methyl-3-(trifluoromethyl)pyrrolidin-1-yl]methanone(2.6 mg, 10%) as white solids

Analytical data for the third eluting diastereomer {arbitrarily assigned(2S, 3R), (5S, 7S) configuration}: SFC R_(T) (Whelk-O1 S,S, 30%methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide,2.5 min method): 1.594 min, 100% purity, 100% ee: ¹H NMR (400 MHz,DMSO-d₆) δ 7.53-7.33 (m, 3H), 7.22 (dt, J=7.8, 1.7 Hz, 2H), 6.22 (dddd,J=56.6, 10.6, 7.1, 1.9 Hz, 1H), 5.83-5.57 (m, 1H), 4.67 (dt, J=106.6,6.7 Hz, 1H), 4.00 (td, J=9.4, 7.9, 3.1 Hz, 1H), 3.91-3.45 (m, 2H),2.85-2.53 (m, 1H), 2.33-1.95 (m, 2H), 1.15 (ddd, J=36.4, 6.5, 1.9 Hz,3H).

LCMS R_(T)=5.07 min, m/z=383.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 30 mins)retention time 5.07 min, ESI+ found [M+H]=383.1

Analytical data for the fourth eluting diastereomer {arbitrarilyassigned (2S, 3S), (5S, 7S) configuration}: SFC R_(T) (Whelk-O1 S,S, 30%methanol+0.1% ammonium hydroxide isocratic elution with Carbon Dioxide,2.5 min method): 1.732 min, 100% purity, 100% ee: ¹H NMR (400 MHz,DMSO-d₆) δ 7.54-7.25 (m, 3H), 7.39-7.11 (m, 2H), 6.22 (dddd, J=56.6,12.7, 7.2, 1.8 Hz, 1H), 5.83-5.56 (m, 1H), 4.70 (dp, J=141.9, 6.6 Hz,1H), 4.09-3.84 (m, 1H), 3.91-3.47 (m, 2H), 2.86-2.53 (m, 1H), 2.33-1.89(m, 2H), 1.30-0.93 (m, 4H). LCMS R_(T)=5.08 min, m/z=383.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 30 mins)retention time 5.08 min, ESI+ found [M+H]=383.1

Example 87

(5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone

Method 17 (28.4 mg, 66% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.47-7.32 (m, 3H), 7.27-7.19 (m, 2H), 6.21(dddt, J=56.6, 7.4, 4.6, 1.7 Hz, 1H), 5.69 (tt, J=6.9, 2.7 Hz, 1H),5.07-4.57 (m, 1H), 3.77 (s, 1H), 3.83-3.63 (m, 1H), 3.54-3.39 (m, 1H),2.97 (d, J=6.8 Hz, 1H), 2.78-2.60 (m, 1H), 2.25 (s, 1H), 2.20-2.01 (m,1H), 1.90 (d, J=13.0 Hz, 2H). LCMS R_(T)=4.52 min, m/z=363.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.52 min, ESI+ found [M+H]=363.1

Example 88

3,4-dihydro-1H-2,7-naphthyridin-2-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (17.1 mg, 43% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.56-8.15 (m, 2H), 7.49-7.34 (m, 3H),7.31-7.14 (m, 3H), 6.23 (ddd, J=56.6, 7.1, 1.9 Hz, 1H), 5.75-5.65 (m,1H), 4.84 (d, J=13.5 Hz, 2H), 3.97-3.82 (m, 1H), 3.86-3.78 (m, 1H),3.83-3.65 (m, 1H), 2.88 (q, J=5.8, 4.1 Hz, 2H), 2.80-2.60 (m, 1H). LCMSR_(T)=2.71 min, m/z=364.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 2.71 min, ESI+ found [M+H]=364.1

Example 89

7,8-dihydro-5H-1,6-naphthyridin-6-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (23.4 mg, 59% yield)

¹H NMR (400 MHz, DMSO-d6) δ 8.40 (dd, J=4.7, 2.0 Hz, 1H), 7.70 (dd,J=7.8, 1.7 Hz, 1H), 7.51-7.33 (m, 3H), 7.30-7.17 (m, 3H), 6.23 (dtd,J=56.5, 6.6, 6.0, 1.9 Hz, 1H), 5.70 (tdd, J=9.6, 7.0, 3.0 Hz, 1H), 4.84(d, J=12.4 Hz, 2H), 4.06-3.85 (m, 2H), 3.85-3.65 (m, 1H), 2.96 (dt,J=8.0, 4.2 Hz, 2H), 2.80-2.62 (m, 1H). LCMS R_(T)=2.81 min, m/z=364.1(M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 2.81 min, ESI+ found [M+H]=364.1

Example 90

rac-(5S,7S)-7-fluoro-N-methyl-N,5-diphenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Method 17 (29.8 mg, 75% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.42-7.13 (m, 6H), 7.15 (s, 2H), 6.80 (s,2H), 6.05 (dd, J=56.7, 6.8 Hz, 1H), 5.54 (s, 1H), 3.81-3.50 (m, 1H),3.38 (s, 3H), 2.64-2.47 (m, 1H). LCMS R_(T)=4.55 min, m/z=337.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.55 min, ESI+ found [M+H]=337.1

Example 91

rac-(5S,7S)—N-(2,2-difluoroethyl)-7-fluoro-N-methyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Method 17 (32.0 mg, 80% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.57-7.23 (m, 3H), 7.23 (ddt, J=8.0, 5.6,1.6 Hz, 2H), 6.63-5.98 (m, 2H), 5.69 (t, J=7.5 Hz, 1H), 4.09 (td,J=15.0, 3.9 Hz, 1H), 3.90 (td, J=15.4, 4.0 Hz, 1H), 3.83-3.58 (m, 1H),3.22-3.00 (m, 3H), 2.80-2.58 (m, 1H). LCMS R_(T)=4.30 min, m/z=325.1(M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.30 min, ESI+ found [M+H]=325.1

Example 92

rac-(5S,7S)-7-fluoro-N-methyl-5-phenyl-N-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

Method 17 (34.2 mg, 68% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.47-7.32 (m, 3H), 7.29-7.16 (m, 2H), 6.22(dddd, J=56.6, 7.2, 4.1, 1.9 Hz, 1H), 5.76-5.65 (m, 1H), 4.74 (qd,J=9.3, 6.1 Hz, 1H), 4.37 (q, J=9.6 Hz, 1H), 3.74 (dddd, J=25.8, 15.5,8.5, 7.2 Hz, 1H), 3.15 (d, J=46.5 Hz, 3H), 2.78-2.61 (m, 1H). LCMSR_(T)=4.62 min, m/z=343.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.62 min, ESI+ found [M+H]=343.1

Example 93

(3-benzylpyrrolidin-1-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (21.1 mg, 42% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.53-7.06 (m, 10H), 6.19 (ddt, J=56.6, 7.2,2.1 Hz, 1H), 5.68 (ddd, J=8.7, 5.1, 1.9 Hz, 1H), 3.95-3.49 (m, 2H),3.46-3.33 (m, 1H), 3.14 (dd, J=12.2, 8.2 Hz, 1H), 2.77-2.59 (m, 4H),2.46 (m, 1H), 1.91 (dq, J=10.9, 6.3 Hz, 1H), 1.77-1.44 (m, 1H). LCMSR_(T)=5.38 min, m/z=391.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 5.38 min, ESI+ found [M+H]=391.1

Example 94

[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]-(1,3,4,5-tetrahydro-2-benzazepin-2-yl)methanone

Method 17 (38.0 mg, 76% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.57-6.76 (m, 9H), 6.45-6.01 (m, 2H), 5.65(dddd, J=15.2, 8.3, 6.9, 2.9 Hz, 1H), 4.96-4.52 (m, 2H), 4.19-3.56 (m,1H), 3.09-2.87 (m, 2H), 2.84-2.56 (m, 1H), 1.74 (d, J=28.7 Hz, 2H). LCMSR_(T)=5.15 min, m/z=377.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 5.15 min, ESI+ found [M+H]=377.1

Example 95

(8-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (34.2 mg, 68% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.48-7.32 (m, 3H), 7.25 (tt, J=7.9, 1.5 Hz,3H), 7.05 (tt, J=13.0, 8.9 Hz, 2H), 6.23 (ddd, J=56.6, 7.2, 1.9 Hz, 1H),5.75-5.66 (m, 1H), 4.82 (d, J=33.7 Hz, 2H), 3.93-3.80 (m, 2H), 3.83-3.65(m, 1H), 2.90 (t, J=5.9 Hz, 2H), 2.79-2.58 (m, 1H). LCMS R_(T)=5.15 min,m/z=381.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 5.15 min, ESI+ found [M+H]=381.1

Example 96

(8-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4] triazol-2-yl]methanone

Method 17 (36.9 mg, 74% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.56-7.24 (m, 3H), 7.39-7.10 (m, 3H),7.19-6.90 (m, 2H), 6.44-6.04 (m, 1H), 5.84-5.25 (m, 2H), 4.63-3.96 (m,1H), 3.56 (m, 2H), 3.02-2.55 (m, 3H), 1.62-1.36 (m, 3H). LCMS R_(T)=5.41min, m/z=395.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 5.41 min, ESI+ found [M+H]=395.1

Example 97

(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (30.8 mg, 81% yield)

¹H NMR (400 MHz, DMSO-d₆) δ 7.48-7.32 (m, 3H), 7.32-6.98 (m, 6H), 6.23(dddd, J=56.6, 7.1, 4.3, 1.9 Hz, 1H), 5.75-5.64 (m, 1H), 5.56 (m, 1H),4.04 (m, 1H), 3.75 (m, 2H), 3.01-2.62 (m, 3H), 1.50 (dd, J=24.3, 6.8 Hz,3H). LCMS R_(T)=5.28 min, m/z=311.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 5.28 min, ESI+ found [M+H]=377.1

Example 98

(3,3-difluoropyrrolidin-1-yl)-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (28.9 mg, 85% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.48-7.33 (m, 3H), 7.25 (ddd, J=7.9, 3.7,1.5 Hz, 2H), 6.23 (ddd, J=56.5, 7.2, 1.9 Hz, 1H), 5.76-5.66 (m, 1H),4.23 (t, J=12.9 Hz, 1H), 4.01 (td, J=7.4, 1.8 Hz, 1H), 3.91 (t, J=13.2Hz, 1H), 3.84-3.64 (m, 2H), 3.43-3.19 (m, 1H), 2.70 (ddt, J=26.8, 15.3,2.3 Hz, 1H), 2.51-2.38 (m, 1H). LCMS R_(T)=4.42 min, m/z=337.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 4.42 min, ESI+ found [M+H]=337.1

Example 99

3,4-dihydro-1H-isoquinolin-2-yl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

Method 17 (30.3 mg, 84% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.48-7.33 (m, 3H), 7.29-7.11 (m, 6H), 6.23(ddd, J=56.6, 7.2, 1.9 Hz, 1H), 5.69 (tdd, J=7.7, 5.8, 3.0 Hz, 1H), 4.78(s, 2H), 3.93-3.65 (m, 3H), 3.44 (s, OH), 2.87 (q, J=6.4 Hz, 2H),2.79-2.62 (m, 1H). LCMS R_(T)=5.03 min, m/z=363.1 (M+H)⁺.

LCMS (5 to 95% acetonitrile in water+0.1% formic acid over 10 mins)retention time 5.03 min, ESI+ found [M+H]=363.1

Example 100 Method B

(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

(23.5 mg, 68% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.48-7.35 (m, 3H), 7.23 (dt, J=8.0, 1.6 Hz,2H), 6.27 (dd, J=7.2, 1.9 Hz, 1H), 6.13 (dd, J=7.1, 1.9 Hz, 1H), 5.69(ddd, J=10.4, 5.5, 2.6 Hz, 1H), 4.15 (dd, J=12.1, 6.4 Hz, 1H), 4.08-3.97(m, 2H), 3.83-3.64 (m, 2H), 2.72-2.54 (m, 2H). LCMS R_(T)=4.39 min,m/z=349.1 [M+H]⁺.

Example 101

3-azabicyclo[3.1.0]hexan-3-yl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

(15.8 mg, 51% yield)

¹H NMR (400 MHz, DMSO-d6) δ 7.41-7.24 (m, 3H), 7.20-7.08 (m, 2H), 6.19(dd, J=7.2, 1.8 Hz, 1H), 6.05 (dd, J=7.2, 1.8 Hz, 1H), 5.60 (ddt, J=8.4,4.6, 2.4 Hz, 1H), 3.85-3.69 (m, 2H), 3.72-3.54 (m, 2H), 3.36 (dd,J=12.1, 4.2 Hz, 1H), 1.58-1.45 (m, 2H), 0.69-0.54 (m, 1H), −0.01 (q,J=4.3 Hz, 1H). LCMS R_(T)=4.26 min, m/z=313.1 [M+H]⁺.

Example 102

(3,3-difluoroazetidin-1-yl)-(6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanone

A mixture of 6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylicacid (30 mg, 0.13 mmol), 1-hydroxybenzotriazole (18 mg, 0.13 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (38 mg, 0.20mmol) and 3,3-difluoroazetidine hydrochloride (34 mg, 0.26 mmol) inN,N-dimethylformamide (3 mL) was stirred at 25° C. for 5 h. The mixturewas filtered and the filtrated was concentrated under reduced pressure.The residue was purified by RP-HPLC (acetonitrile 30-60%/0.05% ammoniahydroxide in water) to afford(3,3-difluoroazetidin-1-yl)-(6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanone(12.7 mg, 31%) as a white solid, ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.27 (m,3H), 7.08 (d, J=8.0 Hz, 2H), 6.59 (s, 1H), 5.54-5.48 (m, 1H), 4.81-4.62(m, 2H), 4.44 (t, J=12.0 Hz, 2H), 3.19-2.94 (m, 3H), 2.55-2.46 (m, 1H).

LCMS R_(T)=0.862 min, m/z=304.0 [M+H]⁺.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 0.862 min, ESI+ found [M+H]=304.0.

Example 103

(3,3-difluoroazetidin-1-yl)-[1-(1,1-difluoropropyl)pyrazolo[4,3-c]pyridin-6-yl]methanone

Step 1: methyl1-(1,1-difluoroallyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate

To a stirred solution of methyl 1H-pyrazolo[4,3-c]pyridine-6-carboxylate(100 mg, 0.56 mmol) in toluene (3 mL) was added triethylamine (114 mg,1.13 mmol) and 3-bromo-3,3-difluoropropene (133 mg, 0.85 mmol). Thereaction was stirred at 60° C. for 19 h. After cooled to roomtemperature, the mixture was diluted with water (10 mL) and extractedwith ethyl acetate (3×10 mL). The combined organic layers were washedwith brine (10 mL), dried and concentrated under reduced pressure. Theresidue was purified by preparative TLC (20% ethyl acetate in petroleumether, Rf=0.5) to afford methyl1-(1,1-difluoroallyl)pyrazolo[4,3-c]pyridine-6-carboxylate (40 mg, 28%)as light yellow solid.

LCMS (0 to 60% acetonitrile in water+0.05% ammonia hydroxide over 3.0mins) retention time 1.186 min, ESI+ found [M+H]=254.1.

Step 2:methyl1-(1,1-difluoropropyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate

A mixture of methyl1-(1,1-difluoroallyl)pyrazolo[4,3-c]pyridine-6-carboxylate (100 mg, 0.39mmol) and palladium (10% on carbon, 60 mg,) in methanol (3 mL) washydrogenated (15 psi) at 25° C. for 3 h and filtered. The filtrate wasconcentrated under reduced pressure to afford crude methyl1-(1,1-difluoropropyl)pyrazolo[4,3-c]pyridine-6-carboxylate (60 mg, 60%)as a white solid.

LCMS (5 to 95% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 1.237 min, ESI+ found [M+H]=256.2.

Step 3: 1-(1,1-difluoropropyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylicacid

A mixture of methyl1-(1,1-difluoropropyl)pyrazolo[4,3-c]pyridine-6-carboxylate (60 mg, 0.24mmol) and lithium hydroxide hydrate (15 mg, 0.35 mmol) intetrahydrofuran (2 mL) and water (0.60 mL) was stirred at 0° C. for 3 hand concentrated under reduce pressure. The residue was diluted withwater (15 mL) and adjusted to pH=4 by addition of aqueous hydrochloricacid (1 N). The resulting mixture was extracted with ethyl acetate (2×15mL). The combined organic layers were washed with brine (10 mL), driedand concentrated under reduced pressure to afford1-(1,1-difluoropropyl)pyrazolo[4,3-c]pyridine-6-carboxylic acid (70 mg,two batches combined, 60%) as light yellow solid which would be useddirectly for next step.

LCMS (0 to 60% acetonitrile in water+0.03% trifluoacetic acid over 2mins) retention time 0.910 min, ESI+ found [M+H]=241.8.

Step 4:(3,3-difluoroazetidin-1-yl)-[1-(1,1-difluoropropyl)pyrazolo[4,3-c]pyridin-6-yl]methanone

A mixture of 1-(1,1-difluoropropyl)pyrazolo[4,3-c]pyridine-6-carboxylicacid (35 mg, 0.15 mmol) and 3,3-difluoroazetidine hydrochloride (23 mg,0.17 mmol) and 1-hydroxybenzotriazole (24 mg, 0.17 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (34 mg, 0.17mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 25° C. for 3 hand concentrated under reduced pressure. The residue (from two batches)was purified by RP-HPLC (acetonitrile 35-65% acetonitrile/0.05% ammoniahydroxide in water) to afford(3,3-difluoroazetidin-1-yl)-[1-(1,1-difluoropropyl)pyrazolo[4,3-c]pyridin-6-yl]methanone(9.5 mg, 21%) as light yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 9.20 (s,1H), 8.49 (s, 2H), 5.14 (t, J=12.0 Hz, 2H), 4.57 (t, J=12.0 Hz, 2H),2.85-2.78 (m, 2H), 1.18 (t, J=7.6 Hz, 3H). LCMS R_(T)=1.137 min,m/z=317.1 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 1.5mins) retention time 1.137 min, ESI+ found [M+H]=317.1.

Example 104

azetidin-1-yl-[rac-(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone

A mixture ofcis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (20 mg, 0.08 mmol), 1-hydroxybenzotriazole (12 mg, 0.08 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (23 mg, 0.12mmol) and azetidine hydrochloride (11 mg, 0.12 mmol) inN,N-dimethylformamide (2 mL) was stirred under 25° C. for 16 h andconcentrated under reduced pressure. The residue was purified by RP-HPLC(25-55% acetonitrile/0.05% ammonia hydroxide in water) to affordazetidin-1-yl-[(5R,7R)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone(6.3 mg, 27%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.34 (m,3H), 7.35-7.23 (m, 2H), 6.16-6.14 (m, 0.5H), 6.02-6.00 (m, 0.5H),5.64-5.58 (m, 1H), 4.63-4.56 (m, 2H), 4.21-4.17 (m, 2H) 3.77-3.68 (m,1H), 2.85-2.73 (m, 1H), 2.41-2.32 (m, 2H). LCMS R_(T)=0.957 min,m/z=287.2 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2mins) retention time 0.957 min, ESI+ found [M+H]=287.2.

Example 105

rac-(5R,7R)-7-fluoro-N,N-dimethyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

A mixture ofcis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylicacid (20 mg, 0.08 mmol), N,N-dimethylamine (2.0 mL, 2 mmol, 1 M intetrahydrofuran),1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (23 mg, 0.12mmol) and 1-hydroxybenzotriazole (11 mg, 0.08 mmol) inN,N-dimethylformamide (2.0 mL) was stirred under 25° C. for 16 h andconcentrated under reduced pressure. The residue was purified by RP-HPLC(23-53% acetonitrile/0.05% ammonia hydroxide in water) to afford(5R,7R)-7-fluoro-N,N-dimethyl-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide(11.92 mg, 54%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.34(m, 3H), 7.24-7.22 (m, 2H), 6.42-6.12 (m, 0.5H), 6.05-5.98 (m, 0.5H),5.59-5.58 (m, 1H), 3.75-3.68 (m, 1H), 3.70 (s, 3H), 3.18 (s, 3H),2.82-2.75 (m, 1H). LCMS R_(T)=0.925 min, m/z=275.3 [M+H]⁺.

LCMS (10 to 80% acetonitrile in water+0.03% trifluoacetic acid over 2mins) retention time 0.925 min, ESI+ found [M+H]=275.3.

RIP1 Kinase Inhibition Assays (Biochemical Assay):

The compounds of the present invention were tested for their capacity toinhibit RIP IK activity as described below.

Enzyme assay: The ability of the receptor interacting protein kinase(RIPK1) to catalyze the hydrolysis of adenosine-5′-triphosphate (ATP) ismonitored using the Transcreener ADP (adenosine-5′-diphosphate) assay(BellBrook Labs). Purified human RIP1 kinase domain (2-375) (50 nM)derived from a baculovirus-infected insect cell expression system isincubated with test compounds for 2 hours in 50 mM Hepes buffer (pH 7.5)containing 30 mM MgCl₂, 1 mM dithiothreitol, 50 uM ATP, 0.002% Brij-35,and 0.5% dimethyl sulfoxide (DMSO). Reactions are quenched by theaddition of IX Bell Brooks Stop buffer B (20 mM Hepes (ph7.5), 40 mMethylenediaminetetraacetic acid and 0.02% Brij-35) containing anadditional 12 mM EDTA and 55 ug/mL ADP2 antibody and 4 nMADP-AlexaFluor® 633 tracer. The tracer bound to the antibody isdisplaced by the ADP generated during the RIP IK reaction, which causesa decrease in fluorescence polarization that is measured by laserexcitation at 633 nm with a FP microplate reader M1000. Fractionalactivity was plotted against test article concentration. Using GenedataScreener software (Genedata; Basel, Switzerland), the data were fit tothe tight-binding apparent inhibition constant (K₁ ^(app)) Morrisonequation [Williams, J. W. and Morrison, J. F. (1979) The kinetics ofreversible tight-binding inhibition. Methods Enzymol 63: 437-67], Thefollowing equation was used to calculate fractional activity and K_(i)^(app):

${{Fractional}\mspace{14mu}{activity}} = {\frac{v_{i}}{v_{o}} = {1 - \frac{\left( {\lbrack E\rbrack_{T} + \lbrack I\rbrack_{T} + K_{i}^{app}} \right) - \sqrt{\left( {\lbrack E\rbrack_{T} + \lbrack I\rbrack_{T} + K_{i}^{app}} \right)^{2} - {{4\lbrack E\rbrack}_{T}\lbrack I\rbrack}_{T}}}{{2\lbrack E\rbrack}_{T}}}}$

where [E]_(T) and [I]_(T) are the total concentrations of active enzymeand test article, respectively.

Exemplary compounds of the present invention are provided in thefollowing Tables along with their physiochemical characterization and invitro RIP1 kinase inhibitory activity data. “Method” in the first columnof each table refers to the synthetic method(s) used to prepare eachcompound as shown in the Examples above. In certain examples, chiralcolumn retention times (min) are provided for certain stereoisomers.

TABLE 1 MS Compound RIP1 (m/z) Example # Ki Stereo- retention Method(μM) Structure and Name chemistry ¹H NMR Data time Example 1 Method #10.057

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.45-7.42 (m, 3H),7.28-7.25 (m, 2H), 5.94- 5.89 (m, 1H), 4.98- 4.93 (m, 2H), 4.53 (t, J =12.0 Hz, 2H), 3.90- 3.82 (m, 1H), 3.27- 3.19 (m, 1H). 340.9 0.713 min(3,3-difluoroazetidin-1-yl)- (7,7-difluoro-5-phenyl-5,6-dihydropyrrolo[1,2- b][1,2,4]triazol-2- yl)methanone Example 1a Method#1 SFC 1 0.008

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 7.55-7.35 (m,3H), 7.33-7.13 (m, 2H), 6.11- 5.95 (m, 1H), 4.99- 4.77 (m, 2H),4.59-4.32 (m, 2H), 4.02-3.75 (m, 1H), 3.29- 3.19 (m, 1H). 341.1 5.66 min(3,3-difluoroazetidin-1-yl)- [(5R)-7,7-difluoro-5- phenyl-5,6-dihydropyrrolo[1,2- b][1,2,4]triazol-2- yl]methanone Example 1b Method#1 >10

Single Unknown Stereoisomer ¹H NMR (400 MHz, CD₃OD) δ 7.46- 7.37 (m,3H), 7.30- 7.20 (m, 2H), 5.94-5.86 (m, 1H), 4.96-4.92 (m, 2H), 4.51 (t,J = 12.0 Hz, 2H), 3.91-3.82 (m, 1H), 3.27-3.23 (m, 1H). 341.1 1.024 min(S)-(7,7-difluoro-5-phenyl- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol- 2-yl)(3,3-difluoroazetidin- 1-yl)methanoneExample 2 Method #2 0.478

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.44-7.38 (m, 3H),7.28-7.24 (m, 2H), 6.26- 6.10 (m, 1H), 5.88- 5.84 (m, 1H), 4.95-4.92 (m,2H), 4.51 (t, J = 12.0 Hz, 2H), 3.45- 3.30 (m, 1H), 3.16-3.04 (m, 1H).323.2 0.961 min Example 3 Method #3 0.009

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.44-7.38 (m, 3H),7.28-7.24 (m, 2H), 6.17- 6.02 (m, 1H), 5.65- 5.62 (m, 1H), 4.95-4.92 (m,2H), 4.52 (t, J = 12.0 Hz, 2H), 3.82- 3.68 (m, 1H), 2.86-2.76 (m, 1H).323.1 1.670 min Example 4 Method #4 0.205

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.32 (m, 2H),7.31-7.24 (m, 3H), 4.99- 4.92 (m, 2H), 4.57- 4.47 (m, 3H), 4.45-4.37 (m,1H), 4.32-4.23 (m, 1H), 3.30- 3.24 (m, 1H), 2.75- 2.63 (m, 1H). 304.90.782 min (3,3-difluoroazetidin-1-yl)- (7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol- 2-yl)methanone Example 5 Method #5 0.768

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.43- 7.36 (m, 5H),5.97 (s, 1H), 4.54-4.43 (m, 4H), 4.43- 4.14 (m, 4H). 321.1 1.559 min(3,3-difluoroazetidin-1-yl)- (8-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[5,1- c][1,4]oxazin-2- yl)methanone Example 6 Method #60.722

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (d, J = 6.4 Hz,1H), 7.38 (t, J = 6.8 Hz, 1H), 7.30- 7.18 (m, 2H), 6.18 (s, 1H),4.81-4.73 (m, 2H), 4.57- 4.31 (m, 4H), 4.29- 4.08 (m, 2H). 339.2 1.713min (3,3-difluoroazetidin-1-yl)- [8-(2-fluorophenyl)-6,8- dihydro-5H-[1,2,4]triazolo[5,1- c][1,4]oxazin-2- yl]methanone Example 7 Method #71.982

Single Unknown Stereoisomer ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 7.92(s, 1H), 5.20-5.12 (m, 2H), 5.06 (t, J = 12.0 Hz, 2H), 4.54 (t, J = 12.0Hz, 2H), 1.87 (q, J = 7.6 Hz, 2H), 1.48 (s, 3H), 0.79 (t, J = 7.6 Hz,3H). 283.1 1.699 min Example 8 Method #8 8.69

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 4.98-4.95 (m, 2H),4.90-4.83 (m, 1H), 4.52 (t, J = 12.0 Hz, 2H), 3.03-2.94 (m, 3H),2.88-2.85 (m, 1H), 1.82 (t, J = 19.2 Hz, 3H). 292.9 0.738 min Example 9Method #9 2.655

Single Unknown Stereoisomer ¹H NMR (400 MHz, CD₃OD) δ 7.35- 7.30 (m,2H), 7.30- 7.21 (m, 3H), 6.44 (s, 1H), 4.96- 4.85 (m, 2H), 4.51- 4.47(m, 3H), 4.40-4.28 (m 1H), 4.28-4.20 (m, 1H), 3.14-3.05 (m, 1H), 2.57-2.50 (m, 1H). 304.2 1.040 min Example 10 Method #10 >10

Single Unknown Stereoisomer ¹H NMR (400 MHz, CD₃OD) δ 7.43- 7.36 (m,1H), 7.23- 7.10 (m, 3H), 5.80-5.77 (m, 1H), 4.96-4.86 (m, 2H), 4.48 (t,J = 12.0 Hz, 2H), 3.38-3.31 (m, 1H), 3.19-3.02 (m, 2H), 2.70- 2.67 (m,1H). 323.2 1.738 min Example 11 Method #11 0.009

Single Unknown Stereoisomer ¹H NMR (400 MHz, CD₃OD) δ 7.44- 7.35 (m,1H), 7.22- 7.10 (m, 3H), 5.80-5.77 (m, 1H), 4.94-4.87 (m, 1H), 4.85 4.79(m, 1H), 4.48 (t, J = 12.0 Hz, 2H), 3.36-3.31 (m, 1H), 3.20- 3.01 (m,2H), 2.75- 2.65 (m, 1H). 323.2 1.737 min Example 12 Method #12 0.137

Single Unknown Stereoisomer ¹H NMR (400 MHz, CD₃OD) δ 7.40- 7.37 (m,1H), 7.19- 7.11 (m, 3H), 5.79-5.75 (m, 1H), 4.58-4.53 (m, 2H), 4.19-4.15 (m, 2H), 3.28- 3.26 (m, 1H), 3.13-3.06 (m, 2H), 2.71-2.68 (m, 1H),2.39- 2.31 (m, 2H). 287.0 0.680 min Example 13 Method #13 1.135

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.38 (s, 5H), 6.24 (s,1H), 5.82 (s, 1H), 4.95- 4.88 (m, 2H), 4.48- 4.42 (m, 2H), 4.45-4.37 (m,2H), 4.29-4.17 (m, 2H). 320.1 1.729 min (3,3-difluoroazetidin-1-yl)-(4-phenyl-6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazin- 2-yl)methanoneExample 14 Method #14 0.233

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.47- 7.23 (m, 2H),7.21- 6.94 (m, 2H), 5.02-4.91 (m, 2H), 4.78-4.68 (m, 1H), 4.50 (t, J =12.0 Hz, 2H), 4.44-4.37 (m, 1H), 4.33-4.18 (m, 1H), 3.40- 3.32 (m, 1H),2.74- 2.63 (m, 1H). 323.1 1.626 min Example 15 Method #4 SFC 2 0.066

Single Unknown Stereoisomer 1H NMR (400 MHz, DMSO-d6) δ 7.42-7.23 (m,5H), 4.96-4.72 (m, 2H), 4.61- 4.15 (m, 4H), 3.25- 3.09 (m, 1H),2.73-2.53 (m, 1H). 305.1 4.98 min (3,3-difluoroazetidin-1-yl)-[(7S)-7-phenyl-6,7- dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]methanone Example 16 Method #16 0.105

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.45-7.33 (m, 3H),7.26-7.17 (m, 2H), 5.66- 5.54 (m, 1H), 4.85(m, 2H), 4.45 (t, J = 12.6Hz, 2H), 3.24-3.14 (m, 2H), 3.14- 3.05 (m, 1H), 2.99 (m, 1H). 305.1 4.26min Example 17 Method #16 1.366

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.49-7.29 (m, 3H),7.26-7.15 (m, 2H), 5.64- 5.51 (m, 1H), 4.67- 4.52 (m, 1H), 4.23-4.19 (m,2H), 4.20-4.15 (m, 1H), 3.87- 3.73 (m, 1H), 3.21 (s, 3H), 3.13-3.03 (m,2H), 3.03- 299.1 3.94 min 2.93 (m, 2H). Example 18 Method #16 0.343

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.45-7.31 (m, 3H),7.25-7.17 (m, 2H), 5.64- 5.54 (m, 1H), 4.86- 4.68 (m, 1H), 4.55-4.27 (m,2H), 4.14-3.98 (m, 1H), 3.29- 3.28 (m, 1H), 3.24- 3.15 (m, 1H),3.13-3.04 (m, 287.1 4.01 min 1H), 3.04-2.92 (m, 1H), 2.60- 2.52 (m, 1H).Example 19 Method #16 0.465

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.44-7.31 (m, 3H),7.23-7.16 (m, 2H), 5.56 (m, 1H), 4.58-4.44 (m, 1H), 4.18- 4.06 (m, 1H),4.02- 3.91 (m, 1H), 3.60-3.49 (m, 1H), 3.30-3.14 (m, 2H), 3.12- 3.02 (m,1H), 3.02- 283.1 4.36 min 2.91 (m, 1H), 2.74-2.63 (m, 1H), 1.22-1.15 (m,3H). Example 20 Method #16 0.271

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.43-7.32 (m, 3H),7.26-7.17 (m, 2H), 5.58 (dd, J = 8.3, 5.7 Hz, 1H), 4.55-4.46 (m, 2H),4.15-4.03 (m, 2H), 3.29- 3.27 (m, 1H), 3.17 (m, 1H), 3.13- 3.03 (m, 1H),3.03- 2.93 (m, 1H), 1.64-1.50 (m, 301.1 4.69 min 3H). Example 21 Method#16 1.357

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.45-7.30 (m, 3H),7.26-7.11 (m, 2H), 5.63- 5.50 (m, 1H), 4.55- 4.43 (m, 1H), 4.13-3.94 (m,2H), 3.64-3.53 (m, 1H), 3.30- 3.25 (m, 1H), 3.25- 3.12 (m, 1H),3.12-3.02 (m, 297.1 5.03 min 1H), 3.02-2.91 (m, 1H), 2.58- 2.52 (m, 1H),1.60- 1.49 (m, 2H), 0.87-0.79 (m, 3H). Example 22 Method #16 0.511

Mixture of Enantiomers 287.1 4.17 min azetidin-1-yl-[5-(2-fluorophenyl)-6,7-dihydro- 5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]methanone Example 23 Method #16 0.044

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.44 (m, 1H), 7.33-7.11 (m, 3H), 5.80(m, J = 8.6, 5.6 Hz, 1H), 4.92- 4.79 (m, 2H), 4.45 (m,2H), 3.26- 3.15 (m, 1H), 3.13- 2.94(m, 2H), 2.69- 2.54 (m, 1H). 323.14.64 min Example 24 Method #16 0.194

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.51-7.35 (m, 1H),7.33-7.12 (m, 3H), 5.78 (dd, J = 8.6, 5.6 Hz, 1H), 5.58-5.27 (m, 1H),4.89-4.64 (m, 1H), 4.54- 4.23 (m, 2H), 4.15- 3.93 (m, 1H), 3.25-3.13 (m,1H), 3.13-2.94 (m, 2H), 2.66- 305.1 4.20 min 2.51 (m, 1H). Example 25Method #16 3.6

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 5.1 Hz,1H), 7.45-7.30 (m, 4H), 7.29- 7.18 (m, 2H), 5.56 (dd, J = 8.3, 5.8 Hz,1H), 2.71 (d, J = 4.8 Hz, 3H), 2.69- 2.66 (m, 1H), 2.60- 2.52 (m, 1H)243.1 3.19 min Example 26 Method #16 0.530

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.44-7.30 (m, 3H),7.27-7.05 (m, 2H), 5.64- 5.47 (m, 0H), 4.48- 4.32 (m, 2H), 4.06-3.90 (m,2H), 3.26-2.53 (m, 1H), 2.23 (s, 1H), 1.04 (s, 1H). 269.1 3.64 minazetidin-1-yl-(5-phenyl-6,7- dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl)methanone Example 27 Method #16 2.2

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.45-7.30 (m, 3H),7.25-7.18 (m, 2H), 5.56 (dd, J = 8.3, 5.7 Hz, 1H), 3.19 (dddd, J = 13.0,9.4, 8.3, 4.9 Hz, 1H), 3.14- 3.06 (m, 1H), 3.05 (s, 3H), 3.03-2.96 (m,1H), 2.95 (s, 3H), 2.59-2.52 (m, 1H). 257.1 3.37 min Example 28 Method#16 8.9

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.45-7.31 (m, 3H),7.29-7.15 (m, 2H), 5.62- 4.68 (m, 1H), 3.71 (d, J = 1.0 Hz, 1H), 3.41(ddt, J = 1.5, 1.0, 0.5 Hz, 1H), 3.21-3.05 (m, 3H), 3.04-2.93 (m, 2H),2.88 (dddd, J = 7.9, 4.8, 2.5, 1.4 Hz, 1H), 295.1 3.92 min 1.96 (dd, J =16.4, 4.3 Hz, 2H), 1.43- 1.26 (m, 2H). Example 29 Method #16 5.4

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.44-7.31 (m, 3H),7.24-7.19 (m, 2H), 5.55 (dd, J = 8.3, 5.7 Hz, 1H), 3.61-3.52 (m, 2H),3.52-3.42 (m, 2H), 3.25- 2.86 (m, 3H), 2.61- 2.52 (m, 1H), 1.65-1.56 (m,2H), 1.56-1.38 (m, 4H). 297.1 4.11 min Example 30 Method #16 6.4

Mixture of Enantiomers 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.30 (m, 3H),7.27-7.13 (m, 2H), 5.57 (dd, J = 8.3, 5.7 Hz, 1H), 3.72-3.60 (m, 2H),3.50-3.40 (m, 2H), 3.24- 3.13 (m, 1H), 3.13- 2.90 (m, 2H), 2.61-2.51 (m,1H), 1.94-1.68 (m, 4H). 283.1 3.88 min Example 31 Method #16 SFC 3 7.1

Single Unknown Stereoisomer 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.31 (m,3H), 7.26-7.16 (m, 2H), 5.67- 5.53 (m, 1H), 4.95- 4.76 (m, 2H), 4.45 (t,J = 12.5 Hz, 2H), 3.24-3.05 (m, 3H), 3.05- 2.92 (m, 1H). 305.1 4.49 minExample 32 Method #16 SFC 4 0.066

Single Unknown Stereoisomer 1H NMR (400 MHz, DMSO-d6) δ 7.45-7.31 (m,3H), 7.28-7.17 (m, 2H), 5.60 (dd, J = 8.4, 5.7 Hz, 1H), 4.94-4.79 (m,2H), 4.45 (t, J = 12.6 Hz, 2H), 3.25- 3.11 (m, 1H), 3.15-2.91 (m, 2H),2.61-2.45 (m, 1H). 305.1 4.49 min Example 33 1.4

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d6) δ 7.49-7.36 (m, 1H),7.37-7.12 (m, 3H), 5.76 (dd, J = 8.6, 5.6 Hz, 1H), 3.24-3.16 (m, 1H),3.04 (s, 3H), 2.95 (s, 3H), 2.87 (m, 2H), 2.59 (m, 1H). 275.1 3.49 minExample 34 3.4

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d6) δ 7.50-7.36 (m, 1H),7.34-7.09 (m, 3H), 5.77 (dd, J = 8.6, 5.5 Hz, 1H), 3.71-3.57 (m, 2H),3.44 (m, 2H), 3.17 (m, 1H), 3.14-2.98 (m, 2H), 2.58 (m, 1H), 1.97-1.69(m, 4H). 301.1 3.98 min Example 35 1.3

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.41-7.38 (m, 3H),7.26-7.25 (m, 2H), 6.25- 6.23 (m, 0.5H), 6.11-6.09 (m, 0.5H), 5.87-5.83(m, 1H), 5.47- 5.45 (m, 0.5H), 5.32-5.30 (m, 0.5H), 4.86-4.80 (m, 1H),4.70- 4.58 (m, 1H), 4.55-4.45 (m, 1H), 4.25-4.19 (m, 1H), 3.43- 3.30 (m,1H), 304.9 0.772 min 3.15-3.07 (m, 1H). Example 36 0.004

Single Unknown Stereoisomer ¹H NMR (400 MHz, CD₃OD) δ 7.41-7.37 (m, 3H),7.25-7.23 (m, 2H), 6.15 (d, J = 6.8 Hz, 0.5H), 6.02 (d, J = 7.2 Hz,0.5H), 5.62- 5.61 (m, 1H), 4.95-4.90 (m, 2H), 4.50 (t, J = 12.0 Hz, 2H),3.76-3.68 (m, 1H), 2.85-2.74 (m, 1H). 323.2 0.969 min Example 37 1.4

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.41-7.35 (m, 2H),7.21-7.17 (m, 2H), 6.28 (s, 1H), 6.11 (s, 1H), 4.95-4.90 (m, 3H),4.45-4.17 (m, 5H). 338.1 1.802 min (3,3-difluoroazetidin-1-yl)-[4-(2-fluorophenyl)-6,7- dihydro-4H-pyrazolo[5,1- c][1,4]oxazin-2-yl]methanone Example 38 0.048

Single Unknown Stereoisomer ¹H NMR (400 MHz, CD₃OD) δ 7.44-7.42 (m, 3H),7.27-7.25 (m, 2H), 5.93- 5.88 (m, 1H), 4.73-4.58 (m, 2H), 4.27-4.19 (m,2H), 3.87- 3.83 (m, 1H), 3.31-3.24 (m, 1H), 1.67-1.59 (m, 3H). 336.90.829 min Example 39 0.032

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.37 (m, 3H),7.27-7.25 (m, 2H), 6.16- 6.14 (m, 0.5H), 6.02-6.00 (m, 0.5H), 5.65-5.59(m, 1H), 5.46- 5.44 (m, 0.5H), 5.31-5.30 (m, 0.5H), 4.86-4.84 (m, 1H),4.68- 4.59 (m, 1H), 4.53-4.41 (m, 1H), 4.26-4.15 (m, 1H), 3.77- 305.20.908 min 3.69 (m, 1H), 2.87-2.73 (m, 1H). Example 40 0.92

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 4.99-4.92 (m, 3H), 4.52(t, J = 12.0 Hz, 2H), 3.03-2.84 (m, 4H), 2.27-2.07 (m, 2H), 1.12 (t, J =7.2 Hz, 3H). 307.1 0.932 min (3,3-difluoroazetidin-1-yl)-[5-(1,1-difluoropropyl)-6,7- dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-yl]methanone Example 41 8

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.49-7.28 (m, 5H),6.01 (s, 1H), 4.46-4.37 (m, 1H), 4.36-4.27 (m, 2 H), 4.23- 4.14 (m, 1H),3.01 (s, 3H), 2.95 (s, 3H). 273.1 3.31 min N,N-dimethyl-8-phenyl-6,8-dihydro-5H- [1,2,4]triazolo[5,1- c][1,4]oxazine-2- carboxamideExample 42 2.1

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.50-7.26 (m, 5H),6.03 (s, 1H), 5.51-5.30 (m, 1H), 4.87-4.58 (m, 1H), 4.50- 3.97 (m, 6H),3.17 (d, J = 5.2 Hz, 1H). 304.1 3.64 min (3-fluoroazetidin-1-yl)-(8-phenyl-6,8-dihydro-5H- [1,2,4]triazolo[5,1- c][1,4]oxazin-2-yl)methanone Example 43 5

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.53-7.33 (m, 2H),7.32-7.17 (m, 2H), 6.17 (s, 1H), 4.48-4.28 (m, 3H), 4.29- 4.16 (m, 1H),2.99 (s, 3H), 2.94 (s, 3H). 291.1 3.26 min 8-(2-fluorophenyl)-N,N-dimethyl-6,8-dihydro-5H- [1,2,4]triazolo[5,1- c][1,4]oxazine-2-carboxamide Example 44 4.8

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.56-7.32 (m, 2H),7.33-7.14 (m, 2H), 6.17 (s, 1H), 4.47-4.15 (m, 4H), 3.43- 3.34 (m, 2H),3.30- 3.25 (m, 3H), 1.22-0.94 (m, 6H). 319.1 4.02 min N,N-diethyl-8-(2-fluorophenyl)-6,8-dihydro- 5H-[1,2,4]triazolo[5,1- c][1,4]oxazine-2-carboxamide Example 45 2.3

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.55-7.43 (m, 1H),7.43-7.35 (m, 1H), 7.32- 7.18 (m, 2H), 6.18 (s, 1H), 5.51-5.27 (m, 1H),4.79- 4.61 (m, 1H), 4.49- 4.27 (m, 5H), 4.27-4.16 (m, 1H), 4.12-3.96 (m,1H). 321.1 3.67 min (3-fluoroazetidin-1-yl)-[8- (2-fluorophenyl)-6,8-dihydro-5H- [1,2,4]triazolo[5,1- c][1,4]oxazin-2- yl]methanone Example46 0.917

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.43-7.37 (m, 3H),7.27-7.25 (m, 2H), 5.88 (d, J = 6.0 Hz, 1H), 5.47-5.45 (m, 0.5H),5.32-5.30 (m, 0.5H), 4.85- 4.82 (m, 1H), 4.63-4.47 (m, 2H), 4.24-4.18(m, 1H), 2.98- 2.94 (m, 1H), 2.67-2.64 (m, 1H), 1.29-1.23 299.0 0.767min (m, 1H), 0.82- 0.79 (m, 1H). Example 47 0.195

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.35 (m, 3H),7.27-7.24 (m, 2H), 5.88 (d, J = 6.4 Hz, 1H), 4.96-4.91 (m, 2H), 4.49 (t,J = 12.0 Hz, 2H), 2.97-2.94 (m, 1H), 2.68-2.65 (m, 1H), 1.28- 1.23 (m,1H), 0.83-0.79 (m, 1H). 317.1 0.808 min Example 48 0.071

Single Unknown Stereoisomer ¹H NMR (400 MHz, CD₃OD) δ 7.45-7.38 (m, 3H),7.26-7.24 (m, 2H), 5.93- 5.88 (m, 1H), 5.47-5.45 (m, 0.5H), 5.32-5.30(m, 0.5H), 4.92- 4.90 (m, 1H), 4.65-4.59 (m, 1H), 4.52-4.42 (m, 1H),4.26- 4.19 (m, 1H), 3.87-3.83 (m, 1H), 3.31-3.21 (m, 1H). 323.1 1.724min

TABLE 2 MS Compound RIP1 (m/z) Example # Ki Stereo- retention Method(μM) Structure and Name chemistry ¹H NMR Data time Example 49 Method 165

Single Known Stereoisomer ¹H NMR (400 MHz, CD₃OD) δ 5.30-5.26 (m, 1H),4.99-4.92 (m, 2H), 4.56- 4.50 (m, 2H), 3.13-3.02 (m, 23), 2.88-2.87 (m,1H) 297.1 1.294 min Example 50 Method 17 1.6

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.49- 7.32 (m, 3H),7.29- 7.16 (m, 2H), 6.21 (ddt, J = 56.5, 7.2, 1.9 Hz, 1H), 5.70 (ddd, J= 9.0. 6.7, 3.0 Hz, 1H), 4.72 (dt, J = 13.1, 9.7 Hz, 1H), 4.45 (td, J =9.7, 5.4 Hz, 1H), 4.29 (t, J = 9.9 Hz, 1H), 4.02 (dd, J = 10.7.5, 4 Hz,1H), 3.87-3.55 (m, 2H), 2.85-2.54 (m, 1H). 355.1 4.59 min Example 51Method 17 0.100

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.49- 7.32 (m, 3H),7.27- 7.11 (m, 2H), 6.59- 6.09 (m, 2H), 5.69 (ddd, J = 8.9. 6.7, 3.0 Hz,1H), 4.56 (q, J = 9.0 Hz, 1H), 4.38 (td, J = 11.0.5.6 Hz, 1H), 4.14 (t,J = 9.7 Hz, 1H), 3.95 (dd, J = 10.5, 5.5 Hz, 1H), 3.72 (dddd, J = 26.2,15.5, 8.5, 7.1 Hz, 1H), 3.24-3.05 (m, 1H), 2.79-2.58(m, 1H). 337.1 4.22min Example 52 Method 17 0.005

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (dddd, J =10.6, 8.6, 6.7, 3.6 Hz, 3H), 7.31- 7.16 (m, 2H), 6.78- 6.02 (m, 2H),5.70 (ddd, J = 8.8, 6.7, 2.8 Hz, 1H), 5.32-4.62 (m, 1H), 4.38 (dd, J =8.5, 7.0 Hz, 1H), 4.11- 3.84 (m, 1H), 3.73 (dddd, J = 26.0. 15.4. 8.5,7.1 Hz, 1H), 2.81- 2.58 (m, 1H), 2.48- 2.35 (m, 1H), 2.34- 2.17 (m, 1H).337.1 10.53 min Example 53 Method 17 0.009

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 7.47- 7.32 (m,3H), 7.28- 7.18 (m, 2H), 6.80- 6.08 (m, 2H), 5.70 (td, J = 8.8, 7.7, 2.8Hz, 1H), 5.18-4.62 (m, 1H), 4.39 (dt, J = 9.1, 6.5 Hz, 1H), 3.98 (dtd, J= 38.7, 9.5. 6.0 Hz, 1H), 3.73 (dddd, J = 26.1, 15.5, 8.5, 7.1 Hz, 1H),2.78- 2.51 (m, 1H), 2.42 (dddd, J = 15.6, 11.7, 8.5, 5.7 Hz, 1H), 2.27(dddd, J = 11.5, 8.7, 6.1, 2.7 Hz, 1H). 337.1 10.48 min Example 54Method 17 0.011

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 7.53- 7.33 (m,3H), 7.24 (ddd, J = 7.8, 3.7, 1.5 Hz, 2H), 6.22 (ddd, J = 56.5, 7.2, 1.9Hz, 1H), 5.70 (td, J = 8.0, 4.2 Hz, 1H), 4.22 (t, J = 12.9 Hz, 1H),4.05- 3.96 (m, 1H), 3.91 (t, J = 13.2 Hz, 1H), 3.85-3.61 (m, 2H), 2.69(ddt, J = 26.8, 15.2, 2.4 Hz, 1H), 2.49-2.31 (m, 2H). 337.1 4.42 minExample 55 Method 17 3.9

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.47- 7.33 (m, 3H),7.27- 7.18 (m, 2H), 6.36- 6.03 (m, 1H), 5.68 (dddd, J = 18.3, 15.5, 8.8,3.7 Hz, 1H), 4.39 (qd, J = 9.5, 6.4 Hz, 1H), 3.93-3.67 (m, 2H),3.57-3.38 (m, 2H), 3.29-3.21 (m, 3H), 2.78-2.61 (m, 1H), 1.39 (dd, J =6.6, 1.4 Hz, 1H), 1.11 (dd, J = 12.5, 6.6 Hz, 1H). 387.2 4.89 minExample 56 Method 17 0.520

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 7.56- 7.05 (m,5H), 6.50- 5.95 (m, 2H), 5.69 (ddd, J = 8.4, 6.7, 3.0 Hz, 1H), 4.14 (td,J = 14.6, 4.0 Hz, 1H), 3.91 (tdd, J = 14.8, 4.1, 2.7 Hz, 1H), 3.83- 3.61(m, 3H), 3.49 (dt, J = 38.7, 5.6 Hz, 2H), 3.11 (s, 3H), 2.69 (ddtd, J =23.7, 13.9.3.3, 1.8 Hz. 1H). 369.2 4.57 min Example 57 Method 17 0.510

Mixture of Enantiomers 385.1 4.51 min Example 58 Method 17 0.570

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.47- 7.32 (m, 3H),7.26- 7.18 (m, 2H), 6.56- 6.03 (m, 2H), 5.80- 5.62 (m, 1H), 4.24- 3.55(m, 4H), 2.92 (s, 1H), 2.80-2.50(m, 1H), 0.91-0.35 (m, 3H). 351.1 4.68min Example 59 Method 17 2.2

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.54- 7.25 (m, 3H),7.33- 7.10 (m, 2H), 6.23 (ddd, J = 56.6, 7.1, 1.7 Hz, 1H), 5.84- 5.60(m, 1H), 4.95- 4.19 (m, 2H), 3.75 (ddt, J = 26.2, 15.5, 7.8 Hz, 1H),2.92 (s, 1H), 2.84-2.45 (m, 1H), 0.97-0.43 (m, 4H). 369.1 5.01 minExample 60 Method 17 0.017

Mixture of Diastereomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.53- 7.31 (m, 3H),7.23 (td, J = 7.9, 1.9 Hz, 2H), 6.63-6.07 (m, 2H), 5.70 (ddd, J = 8.8,5.4, 2.8 Hz, 1H), 5.32-4.61 (m, 1H), 4.39 (dp, J = 9.6, 3.4 Hz, 1H),4.08-3.87 (m, 1H), 3.73 (dddd, J = 26.1, 15.5. 8.5, 7.2 Hz, 1H), 2.78-2.61 (m, 1H), 2.51- 2.34(m, 1H), 2.33- 2.21 (m, 1H). 337.1 4.46 minExample 61 Method 17 3.2

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.46- 7.30 (m, 3H),7.23- 7.15 (m, 2H), 6.20 (ddd, J = 56.7, 7.1, 1.7 Hz, 1H), 5.68 (ddd, J= 8.8, 6.7, 2.8 Hz, 1H), 3.73 (dddd, J = 26.6. 15.5. 8.5, 7.1 Hz, 1H),2.76- 2.51 (m, 3H), 0.60 (m, 8H). 327.2 4.40 min Example 62 Method 170.130

Mixture of Diastereomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.52- 7.31 (m, 4H),7.26 (dt, J = 8.7, 3.1 Hz, 2H), 6.42-5.94 (m, 2H), 5.71 (t, J = 6.6 Hz,1H), 5.11-4.91 (m, 1H), 5.05-4.71 (m, 1H), 4.37 (dq, J = 13.1, 6.6 Hz,1H), 4.26-4.06 (m, 1H), 4.02-3.62 (m, 2H), 2.87-2.57 (m, 1H), 1.50-1.21(m, 3H). 367.2 4.05 min Example 63 Method 17 2.3

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.52- 7.33 (m, 3H),7.26 (ddd, J = 8.0, 3.5, 1.5 Hz, 2H), 6.23 (ddt, J = 56.5, 7.2, 2.3 Hz,1H), 5.78-5.63 (m, 1H), 4.94 (s, 1H), 4.81 (d, J = 2.8 Hz, 1H),4.19-4.01 (m, 4H), 3.74 (ddt, J = 25.8. 15.5, 7.8 Hz, 1H), 2.79-2.62 (m,1H), 2.12 (d, J = 8.8 Hz, 3H). 367.2 4.01 min Example 64 Method 17 0.004

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 7.47- 7.33 (m,3H), 7.23 (ddd, J = 7.4, 3.8, 1.5 Hz, 2H), 6.59-5.98 (m, 2H), 5.70 (ddt,J = 9.4, 6.5, 2.9 Hz, 1H), 5.16-4.43 (m, 1H), 3.86-3.62 (m, 3H),2.77-2.61 (m, 1H), 2.16-1.79 (m, 4H). 351.1 4.72 min Example 65 Method17 0.036

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 7.47- 7.33 (m,3H), 7.22 (tt, J = 8.5. 1.6 Hz, 2H), 6.51-5.99 (m, 2H), 5.70 (ddd, J =9.5, 7.0, 3.0 Hz, 1H), 5.12- 4.38 (m, 1H), 3.88- 3.61 (m, 3H), 2.77-2.60 (m, 1H), 2.16- 1.78 (m, 4H). 351.2 4.71 min Example 66 Method 170.015

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 7.48- 7.34 (m,4H), 7.30- 7.23 (m, 2H), 6.39- 6.00 (m, 2H), 5.70 (dtd, J = 8.9, 6.2,2.9 Hz, 1H), 5.02 (s, 1H), 4.88 (d, J = 2.2 Hz, 1H), 4.27-4.00 (m, 4H),3.75 (dddd, J = 26.3, 14.6, 8.9, 7.3 Hz, 1H), 2.71 (ddd, J = 26.7, 15.3,2.6 Hz, 1H). 353.2 3.84 min Example 67 Method 17 0.005

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (ddd, J =25.5, 4.7, 1.6 Hz, 1H), 7.61 (ddd, J = 7.8, 4.6, 1.6 Hz, 1H), 7.48-7.33(m, 3H), 7.30-7.19 (m, 3H), 6.37-6.08 (m, 1H), 5.70 (dtd, J = 8.5, 5.6,3.0 Hz, 1H), 4.83 (d, J = 29.7 Hz, 2H), 4.03-3.84 (m, 2H), 3.84-3.63 (m,1H), 2.89 (t, J = 5.9 Hz, 2H), 2.79- 2.62 (m, 1H). 364.2 3.44 minExample 68 Method 17 0.049

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.58- 7.26 (m, 3H),7.38- 7.11 (m, 2H), 7.12 (d, J = 1.2 Hz, 1H), 6.89 (dd, J = 14.9, 1.3Hz, 1H), 6.23 (ddd, J = 56.6, 7.2, 1.9 Hz, 1H), 5.70 (tt, J = 7.3, 3.4Hz, 1H), 4.87 (d, J = 63.2 Hz, 2H), 4.09 (dt, J = 12.6, 3.7 Hz, 4H),3.91-3.58 (m, 1H), 2.71 (ddt, J = 26.7, 15.2, 2.4 Hz, 1H). 353.2 2.44min Example 69 Method 17 0.052

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.55- 7.26 (m, 4H),7.26 (dd, J = 7.4, 2.9 Hz, 2H), 6.42-5.97 (m, 2H), 5.70 (ddt, J = 9.2,5.7, 2.9 Hz, 1H), 5.02 (s, 1H), 4.88 (d, J = 1.9 Hz, 1H), 4.29- 4.00 (m,4H), 3.75 (ddt, J = 25.8, 15.5, 7.8 Hz, 1H), 2.82- 2.61 (m, 1H). 353.23.83 min Example 70 Method 17 0.150

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.54- 7.25 (m, 3H),7.23 (tt, J = 6.6, 2.0 Hz, 2H), 6.41-6.03 (m, 1H), 5.69 (td, J = 8.2,7.6, 2.9 Hz, 1H), 5.33 (dt, J = 53.6, 4.5 Hz, 1H), 4.54 (dp, J = 126.8,7.2, 6.8 Hz, 1H), 4.22- 3.62 (m, 3H), 2.84- 2.59 (m, 1H), 2.46- 2.12 (m,1H), 1.96 (ddd, J = 28.5, 19.6, 14.5 Hz, 1H), 1.40- 1.02 (m, 3H). 333.24.36 min Example 71 Method 17 0.690

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.59- 7.31 (m, 3H),7.28- 7.11 (m, 2H), 6.20 (ddt, J = 56.6, 7.2, 2.0 Hz, 1H), 5.68 (ddt, J= 8.6, 5.7, 2.7 Hz, 1H), 4.86-4.67 (m, 1H), 4.45 (s, 1H), 4.12 (dd, J =7.1, 3.8 Hz, 1H), 3.90-3.41 (m, 3H), 3.31 (s, 2H), 2.84-2.52 (m, 1H),2.07-1.65 (m, 3H). 331.2 3.65 min Example 72 Method 17 3.9

Mixture of Diastereomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.47- 7.32 (m, 3H),7.29- 7.18 (m, 2H), 6.22 (dddd, J = 56.5, 7.2, 3.5, 1.9 Hz, 1H), 5.74-5.65 (m, 1H), 5.04 (t, J = 5.5 Hz, 1H), 4.87 (s, 1H), 4.48- 4.29 (m,2H), 4.10 (ddt, J = 31.6, 21.2, 10.7 Hz, 1H), 3.86- 3.63 (m, 1H), 3.59(q, J = 5.1 Hz, 1H), 3.43- 3.17 (m, 2H), 2.78- 2.61 (m, 1H). 366.9 4.06min Example 73 Method 17 0.082

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (dddd, J = 12.0.7.2, 5.9, 2.2 Hz, 3H), 7.29- 7.19 (m, 2H), 6.22 (dddd, J = 56.5, 7.2,3.3, 1.9 Hz, 1H), 5.70 (ddt, J = 8.8, 5.7, 2.7 Hz, 1H), 5.19 (s, 1H),4.75-4.51 (m, 2H), 4.55-4.32 (m, 1H), 4.29-4.06 (m, 1H), 3.92-3.64 (m,1H), 2.% -2.61 (m, 2H), 2.50-2.37 (m, 1H). 368.9 4.75 min Example 74Method 17 0.024

Mixture of Enantiomers ¹HNMR (400 MHz, DMSO-d₆) δ 8.38 (dddd, J = 25.7,4.7, 1.7 Hz, 1H), 7.61 (ddd, J = 7.7, 4.8. 1.6 Hz, 1H), 7.48-7.32 (m,3H), 7.30-7.19 (m, 3H), 6.37-6.11 (m, 1H), 5.75-5.65 (m, 1H), 4.83 (d, J= 29.7 Hz, 2H), 3.99- 3.80 (m, 2H), 3.85- 3.65 (m, 1H), 2.95- 2.85 (m,2H), 2.79- 2.63 (m, 1H). 363.9 3.44 min Example 75 Method 17 0.290

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 8.43- 8.29 (m, 2H),7.48- 7.33 (m, 3H), 7.32- 6.99 (m, 3H), 6.23 (ddd, J = 56.6, 7.6, 2.5Hz, 1H), 5.70 (qd, J = 8.1, 3.1 Hz, 1H), 4.92- 4.76 (m, 2H), 4.03- 3.64(m, 3H), 2.88 (t, J = 5.9 Hz, 2H), 2.79-2.63 (m, 1H). 363.9 2.65 minExample 76 Method 17 0.031

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 7.48- 7.33 (m,3H), 7.30- 6.97 (m, 6H), 6.23 (ddd, J = 56.6, 7.2, 1.9 Hz, 1H), 5.70(dq, J = 7.1, 3.2 Hz, 1H), 4.78 (s, 2H), 3.92- 3.65 (m, 3H), 2.87 (q, J= 6.4 Hz, 2H), 2.79- 2.62 (m, 1H). 363.1 5.03 min Example 77 Method 170.061

Mixture of Diastereomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.47- 7.33 (m, 3H),7.38- 7.15 (m, 4H), 7.01- 6.89 (m, 3H), 6.35- 6.04 (m, 1H), 5.75- 5.62(m, 1H), 5.09 (qd, J = 4.5, 2.4 Hz, 1H), 4.07-3.89 (m, 1H), 3.84-3.51(m, 4H), 2.77-2.58 (m, 1H), 2.29-2.05 (m, 2H). 393.1 5.08 min Example 78Method 17 0.060

Mixture of Diastereomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.57- 7.23 (m, 3H),7.22 (ddt, J = 8.5, 5.3, 1.5 Hz, 2H), 6.68-5.90 (m, 2H), 5.70 (td, J =7.7, 6.5, 2.8 Hz, 1H), 4.69-4.33 (m, 1H), 3.96-3.54 (m, 3H), 2.87-2.50(m, 1H), 2.25-1.63 (m, 4H). 351.1 4.71 min Example 79 Method 17 0.790

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.47- 7.28 (m, 3H),7.28- 7.19 (m, 2H), 6.37- 6.07 (m, 1H), 5.74- 5.63 (m, 1H), 4.07 (t, J =11.8 Hz, 1H), 3.96 (t, J = 12.0 Hz, 1H), 3.83-3.58 (m, 3H), 2.70 (dddd,J = 26.7, 15.2, 3.1, 1.9 Hz, 1H), 2.09 (qt, J = 13.1, 6.7 Hz, 2H), 1.70(td, J = 6.8, 3.9 Hz, 2H). 351.1 4.50 min Example 80 Method 17 0.100

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.48- 7.33 (m, 4H),7.31- 7.23 (m, 2H), 6.64 (s, 1H), 6.24 (ddd, J = 56.5, 7.1, 1.9 Hz, 1H),5.71 (ddd, J = 8.6, 6.7, 3.1 Hz, 1H), 4.16 (t, J = 6.1 Hz, 2H), 4.02(tq, J = 12.9. 7.3, 6.5 Hz, 2H), 3.76 (dddd. J = 25.1, 15.4, 8.5, 7.2Hz, 1H), 2.80-2.63 (m, 1H), 2.14 (p, J = 6.0 Hz, 2H). 353.1 3.97 minExample 81 Method 17 0.250

Mixture of Diastereomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (s, 1H),7.56-7.26 (m, 3H), 7.38-7.16 (m, 2H), 6.58 (s, 1H), 6.40-6.07 (m, 1H),5.73 (ddt, J = 9.4, 6.1, 2.9 Hz, 1H), 5.35 (q, J = 7.2, 6.3 Hz, 1H),4.19 (t, J = 15.5 Hz, 1H), 4.13-3.86 (m, 1H), 3.76 (dddd, J = 25.9,15.5, 8.0, 6.9 Hz, 1H), 2.88- 2.60 (m, 1H), 2.42 (dh, J = 14.9, 4.8 Hz,2H). 421.1 4.71 min Example 82 Method 17 0.450

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (dtd, J = 12.2,6.8, 2.3 Hz, 3H), 7.28-7.14 (m, 2H), 6.36-6.05 (m, 1H), 5.76-5.67 (m,1H), 5.04 (td, J = 8.4, 4.2 Hz, 1H), 3.89- 3.64 (m, 3H), 2.69 (ddt, J =27.3, 18.9, 2.9 Hz, 1H), 2.18- 2.08 (m, 1H), 2.10- 1.90 (m, 3H). 369.14.94 min Example 83 Method 17 0.350

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (ddtt, J = 12.4,9.5, 7.2, 2.1Hz, 3H), 7.30- 7.11 (m, 2H), 6.38- 6.09 (m, 1H), 5.80- 5.65(m, 1H), 5.04 (td, J = 8.3, 4.1 Hz, 1H), 3.92-3.48 (m, 3H), 2.78-2.61(m, 1H), 2.18-2.08 (m, 1H), 2.06-1.78 (m, 3H). 369.1 4.94 min Example 84Method 17 0.300

Mixture of Diastereomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.49- 7.31 (m, 3H),7.28- 7.14 (m, 2H), 6.36- 6.10 (m, 1H), 5.82- 5.63 (m, 1H), 5.11- 4.98(m, 1H), 3.89- 3.49 (m, 3H), 2.78- 2.61 (m, 1H), 2.18- 2.08 (m, 1H),2.06- 1.90 (m, 3H). 369.1 4.94 min Example 85 Method 17 0.330

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 7.53- 7.33 (m,3H), 7.22 (dt, J = 7.8, 1.7 Hz, 2H), 6.22 (dddd, J = 56.6, 10.6, 7.1,1.9 Hz, 1H), 5.83-5.57 (m, 1H), 4.67 (dt, J = 106.6, 6.7 Hz, 1H), 4.00(td, J= 9.4, 7.9, 3.1 Hz, 1H), 3.91- 3.45 (m, 2H), 2.85- 2.53 (m, 1H),2.33- 1.95 (m, 2H), 1.15 (ddd, J = 36.4, 6.5, 1.9 Hz, 3H). 383.1 5.07min Example 86 Method 17 0.005

Single Unknown Stereoisomer ¹H NMR (400 MHz, DMSO-d₆) δ 7.54- 7.25 (m,3H), 7.39- 7.11 (m, 2H), 6.22 (dddd, J = 56.6, 12.7, 7.2, 1.8 Hz, 1H),5.83- 5.56 (m, 1H), 4.70 (dp, J = 141.9, 6.6 Hz, 1H), 4.09-3.84 (m, 1H),3.91-3.47 (m, 2H), 2.86-2.53 (m, 1H), 2.33-1.89 (m, 2H), 1.30-0.93 (m,4H). 383.1 5.08 min Example 87 Method 17 0.150

Mixture of Diastereomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.47- 7.32 (m, 3H),7.27- 7.19 (m, 2H), 6.21 (dddt, J = 56.6, 7.4, 4.6, 1.7 Hz, 1H), 5.69(tt, J = 6.9, 2.7 Hz, 1H), 5.07-4.57 (m, 1H), 3.77 (s, 1H), 3.83-3.63(m, 1H), 3.54-3.39 (m, 1H), 2.97 (d, J = 6.8 Hz, 1H), 2.78-2.60 (m, 1H),2.25 (s, 1H), 2.20-2.01 (m, 1H), 1.90 (d, J = 13.0 Hz, 2H). 363.1 4.52min Example 88 Method 17 0.054

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 8.56- 8.15 (m, 2H),7.49- 7.34 (m, 3H), 7.31- 7.14 (m, 3H), 6.23 (ddd, J = 56.6, 7.1, 1.9Hz, 1H), 5.75- 5.65 (m, 1H), 4.84 (d, J = 13.5 Hz, 2H), 3.97-3.82 (m,1H), 3.86-3.78 (m, 1H), 3.83-3.65 (m, 1H), 2.88 (q, J = 5.8, 4.1 Hz,2H), 2.80-2.60 (m, 1H) 364.1 2.71 min Example 89 Method 17 0.130

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (dd, J = 4.7,2.0 Hz, 1H), 7.70 (dd, J = 7.8, 1.7 Hz, 1H), 7.51- 7.33 (m, 3H), 7.30-7.17 (m, 3H), 6.23 (dtd, J = 56.5, 6.6, 6.0, 1.9 Hz, 1H), 5.70 (tdd, J =9.6, 7.0, 3.0 Hz, 1H), 4.84 (d, J = 12.4 Hz, 2H), 4.06- 3.85 (m, 2H),3.85- 3.65 (m, 1H), 2.96 (dt, J = 8.0, 4.2 Hz, 2H), 2.80-2.62 (m, 1H)364.1 2.81 min Example 90 Method 17 0.620

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.42- 7.13 (m, 6H),7.15 (s, 2H), 6.80 (s, 2H), 6.05 (dd, J = 56.7, 6.8 Hz, 1H), 5.54 (s,1H), 3.81-3.50 (m, 1H), 3.38 (s, 3H), 2.64-2.47 (m, 1H). 337.1 4.55 minExample 91 Method 17 0.042

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.57- 7.23 (m, 3H),7.23 (ddt, J = 8.0, 5.6, 1.6 Hz, 2H), 6.63-5.98 (m, 2H), 5.69 (t, J =7.5 Hz, 1H), 4.09 (td, J = 15.0, 3.9 Hz, 1H), 3.90 (td, J = 15.4, 4.0Hz, 1H), 3.83-3.58 (m, 1H), 3.22-3.00 (m, 3H), 2.80-2.58 (m, 1H). 325.14.30 min Example 92 Method 17 0.100

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.47- 7.32 (m, 3H),7.29- 7.16 (m, 2H), 6.22 (dddd, J = 56.6, 7.2, 4.1, 1.9 Hz, 1H), 5.76-5.65 (m, 1H), 4.74 (qd, J = 9.3, 6.1 Hz, 1H), 4.37 (q, J = 9.6 Hz, 1H),3.74 (dddd, J = 25.8, 15.5, 8.5, 7.2 Hz, 1H), 3.15 (d, J = 46.5 Hz, 3H),2.78-2.61 (m, 1H). 343.1 4.62 min Example 93 Method 17 0.030

Mixture of Diastereomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.53- 7.06 (m,10H), 6.19 (ddt, J = 56.6, 7.2, 2.1 Hz, 1H), 5.68 (ddd, J = 8.7, 5.1,1.9 Hz, 1H), 3.95-3.49 (m, 2H), 3.46-3.33 (m, 1H), 3.14 (dd, J = 12.2,8.2 Hz, 1H), 2.77-2.59 (m, 4H), 2.46 (m, 1H), 1.91 (dq, J = 10.9, 6.3Hz, 1H), 1.77-1.44 (m, 1H). 391.1 5.38 min Example 94 Method 17 0.160

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.57- 6.76 (m, 9H),6.45- 6.01 (m, 2H), 5.65 (dddd, J = 15.2, 8.3, 6.9, 2.9 Hz, 1H), 4.96-4.52 (m, 2H), 4.19- 3.56 (m, 1H), 3.09- 2.87 (m, 2H), 2.84- 2.56 (m,1H), 1.74 (d, J = 28.7 Hz, 2H). 377.1 5.15 min Example 95 Method 170.018

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.48- 7.32 (m, 3H),7.25 (tt, J = 7.9, 1.5 Hz, 3H), 7.05 (tt, J = 13.0, 8.9 Hz, 2H), 6.23(ddd, J = 56.6, 7.2, 1.9 Hz, 1H), 5.75-5.66 (m, 1H), 4.82 (d, J = 33.7Hz, 2H), 3.93-3.80 (m, 2H), 3.83-3.65 (m, 1H), 2.90 (t, J = 5.9 Hz, 2H),2.79- 2.58 (m, 1H). 381.1 5.15 min Example 96 Method 17 0.057

Mixture of Diastereomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.56- 7.24 (m, 3H),7.39- 7.10 (m, 3H), 7.19- 6.90 (m, 2H), 6.44- 6.04 (m, 1H), 5.84- 5.25(m, 2H), 4.63- 3.96 (m, 1H), 3.56 (m, 2H), 3.02-2.55 (m, 3H), 1.62-1.36(m, 3H). 395.1 5.41 min Example 97 Method 17 0.058

Mixture of Diastereomers ¹HNMR (400 MHz, DMSO-d₆) δ 7.48- 7.32 (m, 3H),7.32- 6.98 (m, 6H), 6.23 (dddd, J = 56.6, 7.1, 4.3, 1.9 Hz, 1H), 5.75-5.64 (m, 1H), 5.56 (m, 1H), 4.04 (m, 1H), 3.75 (m, 2H), 3.01-2.62 (m,3H), 1.50 (dd, J = 24.3, 6.8 Hz, 3H). 377.1 5.28 min Example 98 Method17 0.036

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.48- 7.33 (m, 3H),7.25 (ddd, J = 7.9, 3.7, 1.5 Hz, 2H), 6.23 (ddd, J = 56.5, 7.2, 1.9 Hz,1H), 5.76-5.66 (m, 1H), 4.23 (t, J = 12.9 Hz, 1H), 4.01 (td, J = 7.4.1.8 Hz, 1H), 3.91 (t, J = 13.2 Hz, 1H), 3.84-3.64 (m, 2H), 3.43-3.19 (m,1H), 2.70 (ddt, J = 26.8, 15.3, 2.3 Hz, 1H), 2.51-2.38 (m, 1H). 337.14.42 min Example 99 Method 17 0.013

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.48- 7.33 (m, 3H),7.29- 7.11 (m, 6H), 6.23 (ddd, J = 56.6, 7.2, 1.9 Hz, 1H), 5.69 (tdd, J= 7.7, 5.8, 3.0 Hz, 1H), 4.78 (s, 2H), 3.93-3.65 (m, 3H), 3.44 (s, 0H),2.87 (q, J = 6.4 Hz, 2H), 2.79- 2.62 (m, 1H). 363.1 5.03 min Example 100Method B 0.270

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.48- 7.35 (m, 3H),7.23 (dt, J = 8.0. 1.6 Hz, 2H), 6.27 (dd, J = 7.2, 1.9Hz, 1H), 6.13 (dd,J = 7.1, 1.9 Hz, 1H), 5.69 (ddd, J = 10.4, 5.5, 2.6 Hz, 1H), 4.15 (dd, J= 12.1, 6.4 Hz, 1H), 4.08-3.97 (m, 2H), 3.83-3.64 (m. 2H), 2.72-2.54 (m,2H). 349.1 4.39 min Example 101 Method B 0.082

Mixture of Enantiomers ¹H NMR (400 MHz, DMSO-d₆) δ 7.4- 7.24 (m, 3H),7.20- 7.08 (m, 2H), 6.19 (dd, J = 7.2, 1.8 Hz, 1H), 6.05 (dd, J = 7.2,1.8 Hz, 1H), 5.60 (ddt, J = 8.4, 4.6, 2.4 Hz, 1H), 3.85-3.69 (m, 2H),3.72-3.54 (m, 2H), 3.36 (dd, J = 12.1, 4.2 Hz, 1H), 1.58-1.45 (m, 2H),0.69-0.54 (m, 1H)- 0.01 (q, J = 4.3 Hz, 1H). 313.1 4.26 min Example 1020.240

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.42- 7.27 (m, 3H),7.08 (d, J = 8.0 Hz, 2H), 6.59 (s, 1H), 5.54-5.48 (m, 1H), 4.81-4.62 (m,2H), 4.44 (t, J = 12.0 Hz, 2H), 3.19- 2.94 (m, 3H), 2.55- 2.46 (m, 1H)297.1 1.294 min Example 103 6.7

No Stereo ¹H NMR (400 MHz, CD₃OD) δ 9.20 (s, 1H), 8.49 (s, 2H), 5.14 (t,J = 12.0 Hz, 2H), 4.57 (t, J = 12.0 Hz, 2H), 2.85-2.78 (m, 2H), 1.18 (t,J = 7.6 Hz, 3H) 317.1 1.137 min Example 104 0.031

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.42- 7.34 (m, 3H),7.35- 7.23 (m, 2H), 6.16- 6.14 (m, 0.5H), 6.02- 6.00 (m, 0.5H),5.64-5.58 (m, 1H), 4.63-4.56 (m, 2H), 4.21-4.17 (m, 2H) 3.77-3.68 (m,1H), 2.85-2.73 (m, 1H), 2.41-2.32 (m, 2H). 287.2 0.957 min Example 1050.056

Mixture of Enantiomers ¹H NMR (400 MHz, CD₃OD) δ 7.39- 7.34 (m, 3H),7.24- 7.22 (m, 2H), 6.42- 6.12 (m, 0.5H), 6.05- 5.98 (m, 0.5H),5.59-5.58 (m, 1H), 3.75-3.68 (m, 1H), 3.70 (s, 3H), 3.18 (s, 3H),2.82-2.75 (m, 1H) 275.3 0.925 min

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

1. A method for the treatment of a disease or disorder in a human, themethod comprising administering to the human in need thereof aneffective amount of a compound of formula I Formula (I):

or a pharmaceutically acceptable salt thereof, wherein; R¹ and R²: (a)are each independently selected from the group consisting of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ thioalkyl, C₁-C₆ alkyl-N(R^(N))₂, phenyl, 5 to 6membered heteroaryl, and 4 to 5 membered heterocyclyl; (b) together withthe adjacent amide N, form a 4 to 7 membered unsaturated heterocyclicring optionally substituted by one or two R³, wherein the unsaturatedheterocyclic ring contains zero or one additional heteroatom selectedfrom the group consisting of NR^(N), O and S; or (c) together with theadjacent amide N, form a bicyclic heteroaryl moiety optionallysubstituted by one or two R³, wherein the bicyclic heterocyclic moietycontains zero to three additional heteroatoms selected from the groupconsisting of N, O and S, wherein only one of the additional heteroatomsis O or S; each R³ is independently selected from the group consistingof F, Cl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkyl, and phenoxy; or, when R¹ and R²together with the adjacent amide N form a 6 membered ring, two R³ maytogether form a 1 to 2 carbon bridge or a C₃-C₅ spirocycloalkyl; eachR^(N) is independently selected from the group consisting of H, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy and C₁-C₆ haloalkyl; or two R^(N)may together with the adjacent N form a 4-6 membered ring;

is selected from the group consisting of:

R⁴ is selected from the group consisting of phenyl and 5 to 6 memberedheteroaryl, wherein the heteroaryl has one or two heteroatoms selectedfrom O, S and N, and phenyl may be substituted by 1 to 3 substituentsselected from the group consisting of halogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy and cyano; each R^(5a) andR^(5b) is independently selected from the group consisting of H, F, Cl,C₁-C₆ alkyl, C₃-C₄ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆haloalkoxy; R⁸ is selected from the group consisting of H, halo, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy; andwherein the disease or disorder is selected from the group consisting ofirritable bowel disorder (IBP), irritable bowel syndrome (IBS), Crohn'sdisease, ulcerative colitis, myocardial infarction, stroke, traumaticbrain injury, atherosclerosis, ischemia-reperfusion injury of kidneys,liver and lungs, cisplatin-induced kidney injury, sepsis, systemicinflammatory response syndrome (SIRS), pancreatitis, psoriasis,retinitis pigmentosa, retinal degeneration, chronic kidney disease,acute respiratory distress syndrome (ARDS) and chronic obstructivepulmonary disease (COPD).
 2. The method of claim 1, wherein R¹ and R²together with the adjacent amide N, form a 4 to 6 membered unsaturatedheterocyclic ring optionally substituted by one or two R³, containingzero or one additional heteroatom selected from the group consisting ofO and S.
 3. The method of claim 1, wherein the compound has Formula(Ia):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2;and n is 1, 2 or
 3. 4. The method of claim 3, wherein nisi.
 5. Themethod of claim 3, wherein each R³ is independently selected from thegroup consisting of methyl, ethyl, F and Cl.
 6. The method of claim 5,wherein each R³ is methyl or F.
 7. The method of claim 3, wherein

is selected from the group consisting of:


8. The method of claim 3, wherein

is selected from the group consisting of:


9. The method of claim 1, wherein the compound has Formula (Ib) or (Ic):

or a pharmaceutically acceptable salt thereof, wherein, in eachinstance, the C ring is phenyl or a 5 to 6 membered heteroaryl ring; Zis C or N; each R³ is independently selected from the group consistingof F, Cl, C₁-C₃ alkyl, C₃-C₅ cycloalkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxyand C₁-C₃ haloalkoxy; n is 1 or 2; and m is 0, 1 or
 2. 10. The method ofclaim 9, wherein

are independently selected from the group consisting of:


11. The method of claim 1, wherein R¹ is selected from the groupconsisting of C₁-C₃ alkyl, C₃-C₅ cycloalkyl and C₁-C₃ haloalkyl; and R²is selected from the group consisting of C₁-C₃ alkyl, C₃-C₅ cycloalkyl,C₁-C₄ alkoxy, phenyl and 4 to 5 membered heterocyclyl.
 12. The method ofclaim 11, wherein R¹ is selected from the group consisting of methyl,cyclopropyl, —CH₂CF₂H and —CH₂CF₃; and R² is selected from the groupconsisting of methyl, cyclopropyl, —CH₂CH₂OCH₃, phenyl and oxetan-3-yl.13.-14. (canceled)
 15. The method of claim 1, wherein

is selected from the group consisting of:


16. The method of claim 1, wherein

is selected from the group consisting of:

17.-20. (canceled)